Phase I Trial of Stereotactic Radiosurgery Following Surgical Resection of Brain Metastases

This study is currently recruiting participants.
Verified March 2014 by Emory University
Sponsor:
Information provided by (Responsible Party):
Ian Crocker, MD, Emory University
ClinicalTrials.gov Identifier:
NCT01395407
First received: July 14, 2011
Last updated: March 2, 2014
Last verified: March 2014
  Purpose

Brain metastases are the most common adult intracranial tumor, occurring in approximately 10% to 30% of adult cancer patients, and represent an important cause of morbidity and mortality in this population. The standard of care for solitary brain metastasis is surgery followed by whole brain radiation therapy (WBRT). Without WBRT, there are unacceptably high levels of local failure that occur. Local recurrence rates ranged from approximately 45% at 1 year to 60% at 2 years after resection alone. However, aside from improvements in intra-cranial control, it is well documented that WBRT is associated with serious long term side effects, including significant decline in short term recall by as early as 4 months after treatment.

Many centers are now offering patients stereotactic radiosurgery (SRS) to the cavity after resection alone to improve local control while avoiding the negative effects of WBRT. There have been several retrospective studies on the use of SRS to the resection cavity alone, from which the 1 year actuarial local control rates range from 35% - 82%. The high rate of in-field local failure suggests that the current dosing regimen used may not be high enough for adequate local control. Currently, the highest local control rates are approximately 80%, but there may be room for improvement with increased dose without significantly increasing the risk of side effects.

The investigators propose a trial for patients after surgical resection of solitary brain metastases. The purpose of this trial will be to determine the maximum tolerated dose for single fraction SRS to the resection cavity. There will be three groups based on the resection cavity size. Dose escalation enrollment will be done sequentially within each cohort. You will know which cohort and which specific dose level you are randomized to. After treatment, which will take one day, regardless of cohort, you will be followed closely for treatment outcome and possible side effects. You will be asked to complete three quick surveys at each follow-up appointment regarding quality of life and memory in addition to standard of care surveillance brain MRI and physical exam.


Condition Intervention Phase
Brain Metastasis
Neoplasm
Radiation: Radiosurgery dose escalation
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Stereotactic Radiosurgery Following Surgical Resection of Intra-axial Brain Metastases

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • Maximum Tolerated Dose [ Time Frame: 4 months after intervention ] [ Designated as safety issue: Yes ]
    To assess whether treating a brain resection cavity with this stereotactic radiosurgery is safe and tolerable and to determine the maximum-tolerated radiation dose for SRS to the resection cavity alone with 4-month toxicity as assessed by the RTOG CNS toxicity scale


Secondary Outcome Measures:
  • Local Control [ Time Frame: up to 2 years after intervention ] [ Designated as safety issue: No ]
    Defined as lack of progression of disease in resection cavity as assessed by period MRI scans for up to 2 years after intervention.

  • Distant Control [ Time Frame: up to 2 years after intervention ] [ Designated as safety issue: No ]
    Defined as lack of progression of disease in surrounding brain as assessed by period MRI scans for up to 2 years after intervention

  • Neurocognitive Outcomes [ Time Frame: up to 2 years after intervention ] [ Designated as safety issue: No ]
    Neurosognitive assessment using the Hopkins Verbal Learning Test-Revised (HVLT-R), Mini Mental Status Exam (MMSE) and Cognitive Functioning Subscale of the Medical Outcomes Scale (MOS), administered to the patient periodically for up to 2 years after intervention.

  • Quality of Life [ Time Frame: up to 2 years after intervention ] [ Designated as safety issue: No ]
    Quality of life (QOL) outcomes: using the quality of life questionnaire for the Functional Assessment of Cancer Therapy-Brain (FACT-Br) administered periodically for up to 2 years.


Estimated Enrollment: 54
Study Start Date: July 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A

Cohort A: resection cavity volume up to 4.2 cc (corresponds to 0 - 2 cm diameter).

Dose level Cohort A (Gy)

  1. 21
  2. 23
  3. 25
Radiation: Radiosurgery dose escalation

Cohort A: resection cavity volume up to 4.2 cc (corresponds to 0 - 2 cm diameter).

Cohort B: resection cavity volume > 4.2 cc and ≤ 14.1 cc (2 - 3 cm diameter) Cohort C: resection cavity volume > 14.1 cc and ≤ 35 cc (3 - 4 cm diameter)

Dose level Cohort A (Gy) Cohort B (Gy) Cohort C (Gy)

  1. 21 18 15
  2. 23 20 17
  3. 25 22 19
Experimental: Cohort B

Cohort B: resection cavity volume > 4.2 cc and ≤ 14.1 cc (2 - 3 cm diameter).

Dose level Cohort B (Gy)

  1. 18
  2. 20
  3. 22
Radiation: Radiosurgery dose escalation

Cohort A: resection cavity volume up to 4.2 cc (corresponds to 0 - 2 cm diameter).

Cohort B: resection cavity volume > 4.2 cc and ≤ 14.1 cc (2 - 3 cm diameter) Cohort C: resection cavity volume > 14.1 cc and ≤ 35 cc (3 - 4 cm diameter)

Dose level Cohort A (Gy) Cohort B (Gy) Cohort C (Gy)

  1. 21 18 15
  2. 23 20 17
  3. 25 22 19
Experimental: Cohort C

Cohort C: resection cavity volume > 14.1 cc and ≤ 35 cc (3 - 4 cm diameter).

Dose level Cohort C (Gy)

  1. 15
  2. 17
  3. 19
Radiation: Radiosurgery dose escalation

Cohort A: resection cavity volume up to 4.2 cc (corresponds to 0 - 2 cm diameter).

Cohort B: resection cavity volume > 4.2 cc and ≤ 14.1 cc (2 - 3 cm diameter) Cohort C: resection cavity volume > 14.1 cc and ≤ 35 cc (3 - 4 cm diameter)

Dose level Cohort A (Gy) Cohort B (Gy) Cohort C (Gy)

  1. 21 18 15
  2. 23 20 17
  3. 25 22 19

  Hide Detailed Description

Detailed Description:

Brain metastases are the most common adult intracranial tumor, occurring in approximately 10% to 30% of adult cancer patients, and represent an important cause of morbidity and mortality in this population. The risk of developing brain metastases differs with different primary tumor histologies, with lung cancer accounting for approximately one half of all brain metastases. The prognosis of patients with brain metastases is poor. The median survival time of untreated patients is approximately 1 month. With treatment, the overall median survival time after diagnosis is approximately 4 months. The RTOG recursive partitioning analysis (RPA) describes three prognostic classes, defined by age, Karnofsky Performance Score (KPS), and disease status. The most widely used treatment for patients with multiple brain metastases is whole brain radiation therapy (WBRT). The appropriate use of WBRT can provide rapid attenuation of many neurological symptoms, improve quality of life, extend median survival, and be especially beneficial in patients whose brain metastases are surgically inaccessible or when other medical considerations preclude surgery. The use of adjuvant WBRT after resection or stereotactic radiosurgery (SRS) has been proven to be effective in terms of improving local control of brain metastases, and thus, the likelihood of neurological death is decreased.

The standard of care for solitary brain metastasis is surgery followed by WBRT. In a study by Patchell et al. for solitary brain metastases status post resection, the addition of whole brain radiation significantly reduced local recurrence from approximately 45% to 10% after resection. Although it does not prolong survival or functional independence, this treatment regimen was shown to result in significantly improved loco-regional control. A more recent study from the EORTC randomized patients who underwent gross total resection (GTR) of up to 3 brain metastases to adjuvant WBRT versus observation. Adjuvant WBRT resulted in significantly reduced intracranial failure and neurologic death, however again both overall survival and functionally independent survival were not different. Among the major findings of both of these studies are the unacceptably high levels of local failure that occur after GTR alone. Local recurrence rates ranged from approximately 45% at 1 year to 60% at 2 years after resection.

However, aside from improvements in intra-cranial control, it is well documented that WBRT is associated with serious long term side effects, including significant neurocognitive decline. A randomized study conducted by Chang et al of SRS versus SRS + WBRT for 1 - 3 brain metastases found that addition of WBRT was associated with significantly worse memory recall as early as 4 months. A conclusion of this study was that a regimen of close surveillance and SRS as necessary is preferred over SRS + WBRT because the neurocognitive effects of WBRT may actually be worse than that caused by intracranial disease recurrence.

Many centers are now offering patients SRS to the cavity after resection alone to improve local control while avoiding the negative effects of WBRT. There have been several retrospective studies on the use of SRS to the resection cavity alone, from which the 1 year actuarial local control rates range from 35% - 82%. The radiation necrosis rates from these same studies range from 2% - 6%. In currently unpublished data from Emory University reviewing 63 patients with 65 cavities treated between 01/2007 and 08/2010, the 1 year actuarial local control rate was 78%. Of the 10 local failures, 70% were in-field only, 10% were marginal only, and 20% were both. The high rate of in-field failure suggests that the current dosing regimen used may be insufficient for optimal local control. The current SRS dose constraints used are derived from the phase I trial RTOG 90-05. This study determined the maximum tolerated dose for SRS in previously irradiated patients with unresected brain metastases based on lesion size. The maximum doses currently used may be artificially low for resected patients for several reasons. First, the patient population studied had been previously irradiated which most likely lowered the maximum tolerated dose versus a non-irradiated population. Secondly, the typical planning target volume (PTV) of the resection bed is the cavity with a 1 - 2mm margin. This means that the vast majority of the irradiated PTV is not brain parenchyma, but actually CSF, which should result in a lower radiation necrosis rate for the same dose/volume. Currently, the highest local control rates are approximately 80%, but there may be room for improvement with increased dose without significantly increasing the risk of radiation necrosis.

The investigators propose a prospective phase I trial for patients status post surgical resection of solitary brain metastases. The purpose of this trial will be to determine the maximum tolerated dose for single fraction SRS to the resection cavity. The investigators believe that the current SRS dosing constraints may be too low, and that a larger therapeutic window exists for this patient population. Results from this trial may form the basis of future trials directly comparing WBRT with SRS to the cavity alone following resection of solitary brain metastases. This phase III study would answer the question about as to whether local irradiation is adequate treatment for patients following surgery for metastatic brain disease. Also it is anticipated that QOL measures would be built into the study in an attempt to confirm the data reported by Chang that WBRT is associated with a significant decline in QOL at even early endpoints.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologic proven diagnosis of solid tumor malignancy.
  • Age ≥ 18.
  • RPA class I or class II
  • Mini Mental Status Exam (MMSE) ≥ 18 prior to study entry.
  • Karnofksy Performance Status ≥ 70%
  • Solitary brain metastasis status post gross total surgical resection.(≤ 1 cc of residual enhancing tumor
  • Resection cavity volume on planning scan of ≤ 35 cc.
  • First presentation of brain metastases.

Exclusion Criteria:

  • Previous brain radiotherapy (SRS or WBRT).
  • RPA class III
  • Resection cavity volume > 35 cc.
  • Radiosensitive or non-solid (eg. small cell lung carcinomas, germ cell tumors, leukemias, or lymphomas) or unknown tumor histologies.
  • Concurrent chemotherapy (no chemotherapy starting 14 days before start of radiation to 14 days after completion of radiation).
  • Evidence of leptomeningeal disease by MRI and/or CSF cytology.
  • Current pregnancy
  • More than 6 weeks between resection and radiosurgical procedure
  • No metastases to brain stem, midbrain, pons, or medulla or within 7 mm of the optic apparatus (optic nerves and chiasm).
  • Inability to undergo MRI evaluation for treatment planning and follow-up
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01395407

Contacts
Contact: Shravan Kandula, MD 404-778-3473 skandul@emory.edu

Locations
United States, Georgia
Emory University Hospital Recruiting
Atlanta, Georgia, United States, 30322
Contact: Roshan Prabhu, MD    404-778-3473    rprabhu@emory.edu   
Principal Investigator: Ian Crocker, MD         
Sub-Investigator: Shravan Kandula, MD         
Sub-Investigator: Hui-Kuo Shu, MD, PhD         
Sub-Investigator: Walter Curran, MD         
The Emory Clinic Recruiting
Atlanta, Georgia, United States, 30322
Contact: Shravan Kandula, MD    404-778-3473    skandul@emory.edu   
Principal Investigator: Ian Crocker, MD         
Sub-Investigator: Shravan Kandula, MD         
Sub-Investigator: Hui-Kuo Shu, MD, PhD         
Sub-Investigator: Walter Curran, MD         
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Ian Crocker, MD Emory University
  More Information

Publications:

Responsible Party: Ian Crocker, MD, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT01395407     History of Changes
Other Study ID Numbers: IRB00049695, RADONC1962-11
Study First Received: July 14, 2011
Last Updated: March 2, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Emory University:
Brain
Neoplasm
Neoplasm Metastasis
Radiosurgery

Additional relevant MeSH terms:
Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Brain Neoplasms
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases

ClinicalTrials.gov processed this record on April 17, 2014