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

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 Radiation Therapy
Oncology Group (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 European Organization for Research and Treatment of Cancer
(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 cerebrospinal fluid (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.

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

- Karnofsky Performance Status ≥ 70%

- Single brain metastasis status post surgical resection with ≤ 1 cc of residual
enhancing tumor

- Up to 2 additional intact brain metastases to be treated with stereotactic
radiosurgery (SRS) alone

- Resection cavity volume on planning scan of ≤ 35 cc

- First presentation of brain metastases

- Post-operative MRI within 72 hours of surgical resection

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 8 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