Trial Information

Phase I Trial of Stereotactic Radiosurgery Following Surgical Resection of Intra-axial 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 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.