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Metastases to the brain make up more than half of all
intracranial tumors and occur in 20 to 40 percent of patients with systemic
cancer. Brain metastases are single in about one-third of cases. The term
single brain metastasis is applied to patients with one metastasis in the brain
but makes no inference about the presence or absence of cancer elsewhere in the
body. The term solitary brain metastasis describes the relatively rare
occurrence of a single brain metastasis that is the only known cancer in the
body. The occurrence of brain metastasis is usually associated with a poor
prognosis regardless of therapy. Untreated patients with brain metastases have a
median survival of only about 1 month. Virtually all untreated patients die as a
direct result of the brain tumor. With corticosteroid treatment alone, the
median survival is increased to approximately 2 months. As is true for untreated
patients, most patients treated with corticosteroids alone die as a direct
result of the brain metastases.
The Role of Radiotherapy
Whole-brain radiation therapy (WBRT) increases median survival to 3 to 6 months.
Large retrospective studies have shown that most patients treated with WBRT
ultimately die from progressive systemic cancer and not as a direct result of
the brain metastases. However, the WBRT survival data were derived from studies
containing large numbers of patients with extensive systemic disease and
relatively short expected survivals. In the subgroup of patients whose only
metastases are to the brain, death is more likely to be due to the brain
metastasis than to progressive systemic disease Therefore, in patients with
controlled systemic cancer who develop brain metastases, the treatment of the
brain lesion or lesions is the factor that will most likely determine length of
survival.
A controversy remains regarding whether postoperative radiotherapy should be
given as WBRT (as opposed to focal radiation) or whether radiotherapy is
necessary at all after complete resection of a single metastasis. Postoperative
WBRT is believed by some to be beneficial for treating residual tumor in the
operative site or at other contiguous sites in the brain. However, brain
metastases tend to be discrete masses that can be removed totally with high
frequency. Although other undetected microscopic metastases may exist elsewhere
in the brain, this contention has never been proved either by autopsy analysis
or by clinical studies (retrospective or prospective).
From a theoretical standpoint, the combination of surgery followed by
postoperative radiotherapy should be more effective at eradicating brain
metastases than radiation or surgery alone. For larger tumors, radiotherapy is
most effective at the periphery of the tumor, where cells are relatively small
in number and well oxygenated. In the center of the tumor, where tumor cells are
more numerous and hypoxic conditions usually exist, radiation may fail to
completely destroy tumor cells. Although sterilization of brain metastases by
radiotherapy alone is documented, in most cases residual tumor remains despite
irradiation. Surgery can completely remove all tumor cells; however, residual
tumor remains in about one-third of patients, even after "complete"
surgical resection. Rational treatment plan's combining surgical debulking and
radiotherapy have been developed to overcome the deficiencies of both types of
treatment, and combined therapy has shown promise in patients with a variety of
tumor types.
Five nonrandomized retrospective studies have compared surgery plus
postoperative WBRT to surgery alone in the management of single brain
metastases. These retrospective studies do not establish firmly the efficacy of
postoperative WBRT in the treatment of single metastases, although they suggest
that WBRT may decrease the recurrence rate. Little evidence exists to suggest
that any improvement in overall survival times is achieved by the addition of
WBRT. Current practice is to
use WBRT postoperatively.
The Role of Surgery
Despite the theoretical advantages of combined surgical and
radiation treatment, until recently the role of surgery was unclear because of
an absence of any prospective randomized trials showing the efficacy of surgical
treatment. Many uncontrolled surgical series showed longer survival rates for
surgically treated patients than for historical patient controls treated with
WBRT alone. Retrospective or nonrandomized uncontrolled studies
of patients treated with WBRT (and containing small numbers treated with surgery
plus postoperative WBRT) also generally showed increased survival rates for the
surgically treated patients. However, neither
historical controls nor controls consisting of concurrent unselected patients
treated with WBRT alone are appropriate for comparing the efficacy of surgery
plus WBRT versus WBRT alone. Patients who receive surgical treatment are usually
selected from among patients with controlled or no known systemic disease (and
consequently longer expected survivals), whereas patients treated with WBRT
alone include patients with more extensive disease and generally much poorer
prognoses. Patchell et al. used matched control groups to compare surgery plus
WBRT with WBRT alone. Although this study suggested that surgery was
effective, the study was retrospective and did not use randomized assignment to
treatment groups.
Two randomized prospective studies have been performed to determine the
effectiveness of surgery. Patchell et al. randomly assigned patients with single brain metastases to one
of two treatment groups: (1) the surgical group had complete surgical removal of
the brain metastasis followed by WBRT, and (2) the radiation-alone group had a
stereotactic needle biopsy of the brain lesion followed by WBRT. All patients
received 3600 cGy WBRT. Fifty-four patients were entered into the study;
however, six (11 percent) were found not to have metastatic brain tumors after
resection or biopsy. Local recurrence of the brain metastasis was more common
in the radiation-alone group, 52 percent versus 20 percent (P < .02). Overall
survival was significantly longer (P < .03) in the surgical group (median 40
weeks versus 15 weeks). Quality of life (based on the time that the Karnofsky
score remained (70 percent) was also significantly (P < .006) better in
the surgical group. The 30-day mortality rates were 4 percent in both the
surgical group and the radiation-alone group.
A second randomized study,
conducted as a multi-institutional trial in the Netherlands, randomized 63
patients either to complete surgical resection plus WBRT or to WBRT alone. WBRT
schedules were the same for both treatment arms, consisting of 4000 cGy given
in a nonstandard fractionation scheme of 200 cGy twice per day for 2 weeks (10
treatment days). Survival times were significantly longer for the surgical group
(10 months vs. 6 months), and this patient group also demonstrated a
nonsignificant trend toward longer duration of functional independence.
The results of these two
well-controlled prospective trials clearly show that surgical resection is
beneficial for selected patients. Surgical therapy plus postoperative WBRT is
now the treatment of choice for patients with surgically accessible single brain
metastases.
With any surgical procedure,
operative mortality must be weighed against any possible benefit from surgery.
In older series of patients with single brain metastases who were treated with
surgery, operative mortality rates were in the range of 10 to 34
percent. However, with improvement in surgical technique
(particularly the introduction of microsurgery), computer-assisted stereotactic
surgery, intraoperative ultrasonography, and the widespread use of steroids,
mortality rates in most series reported during the last 10 years have been below
10 percent. Kelly et al. reported no mortality in a series of 45 patients, using
computer-assisted stereotactic techniques. Sundaresan et al. reported a 3
percent mortality.
Standard practice has been to
assume that patients with systemic cancer developing an intracranial lesion
have a brain metastasis. An interesting finding is the high
percentage of patients who proved not to have metastatic brain tumors after
surgery or biopsy. All patients had tissue-proven primary tumors diagnosed
before their entry into the study. Despite having computed tomography (CT) and
magnetic resonance imaging (MRI) findings consistent with single brain
metastases, 11 percent of the total (6/54) did not have metastatic tumors.
Because of the relatively high rate of misdiagnosis of metastatic lesions with
CT scans, even when surgical resection is not recommended, a stereotactic
needle biopsy should usually be done to confirm the diagnosis. This practice
should especially be followed in patients with controlled systemic cancer whose
survival is likely to be dependent on the treatment of the brain lesion. Half
of the patients who were proved not to have brain metastases had potentially
treatable intracranial infectious or inflammatory processes.
Despite the demonstrated
advantage of surgical intervention, however, WBRT alone remains the treatment of
choice for most patients with brain metastases. Single metastases occur in
approximately one-third of patients. Unfortunately, nearly half of the
patients in this group are not candidates for surgery because of the
inaccessibility of the tumor, extensive systemic disease, and other factors.
At most, only 15 to 20 percent of all patients with brain metastases will
benefit from surgical resection. The rest should usually be treated with
radiotherapy.
Chemotherapy
Chemotherapy has been used in
the treatment of brain metastases from a variety of primary tumors; however, the
results have generally been unimpressive, although some small,
controlled series of patients with certain highly chemosensitive tumors
(breast, small cell lung cancer, and germ cell tumors) have been published. At
present, chemotherapy should be used only to treat those metastatic brain
tumors that are known to be chemosensitive, such as lymphoma or small cell
carcinoma.
Stereotactic Radiosurgery
The development of stereotactic
radiosurgery, a method of delivering intense focal irradiation by using a
linear accelerator (LINAC) or multiple cobalt-60 sources (gamma knife), has
again raised the question of the best treatment for both single- and
multiple-metastatic disease. No definitive conclusion can be drawn regarding its efficacy in
the treatment of brain metastases. Several uncontrolled series of highly preselected patients have been published. These
studies suggest that the local control rate for radiosurgery in the treatment of
single metastases may be similar to that achieved by conventional surgery. The
combined results of several reports indicate that radiosurgery
locally controls the growth of 80 to 90 percent of cerebral metastases with a low
risk of radiation necrosis or new neurological deficits. At this time, the
proven conventional therapy for single metastasis is still surgical excision
followed by WBRT. The early reports of series using radiosurgery indicate that
this may be an acceptable method of treatment for both surgically accessible and
inaccessible lesions. To date, however, no well-controlled randomized trial has
been reported comparing radiosurgery with conventional surgery for the treatment
of cerebral metastases.
Surgical Indications
The best results with
surgery are seen in those patients with a single surgically accessible
lesion and either no remaining systemic disease (true solitary metastasis)
or with controlled systemic cancer limited to the primary site only. A study
from the Memorial Sloan-Kettering Cancer Center suggested that survival
rates are significantly increased for patients undergoing resection of brain
metastases from non-small cell lung carcinoma if the primary lung disease is
also resected completely. No correlation was demonstrated between survival
rates and initial cancer stage per se. Also, surgical treatment may be
indicated for those patients without known systemic cancer (to obtain a
tissue diagnosis) and for patients for whom death is imminent because of
the effects of pressure on the brain stem.
Because the median time that
Karnofsky scores remain ≥70 percent is about 2 months in patients treated
with WBRT alone, patients with life expectancies less than that receive
adequate palliation from radiation alone and are unlikely to gain any
benefit from surgery.
Patients with metastasis
from systemic lesions that are highly radiosensitive, such as lymphoma, germ
cell tumors, or leukaemia, should have WBRT as the primary treatment.
However, even those patients with very radiosensitive cancers with a single
brain lesion should be offered diagnostic stereotactic biopsy before
treatment of the brain lesion. Between 5 and 10 percent of brain lesions in
patients with known systemic cancer are not metastases, so tissue
confirmation of cerebral metastasis is necessary for accurate treatment
planning.
Surgical Treatment
The microsurgical removal of
a cerebral metastasis is performed following the same general techniques of
craniotomy and microsurgery that are used for the removal of other
intracranial lesions. However, in planning the surgical procedure, two
features of a cerebral metastasis must be anticipated: (1) the propensity of
a cerebral metastasis to cause substantial cerebral oedema, and (2) the small
size of many metastatic lesions at the time of surgical resection.
Administering corticosteroids preoperatively for at least 48 h to patients
with considerable mass effect will help prevent transdural herniation at
the time of tumor exposure. However, preparatory steroid administration can
also cause the overlying cortical surface to appear normal and can make the
safe localization of a small tumor even more difficult.
Metastatic lesions are often
removed when they are quite small because the extensive cerebral oedema
associated with the lesion rather than the lesion per se has caused early
neurologic symptoms. Likewise, asymptomatic tumors discovered as part of
the survey evaluation of patients with a newly discovered systemic cancer
may be very small. These small lesions, if not superficial, may be quite
difficult to locate under a normal-appearing cortical surface.
Computer-assisted stereotactic techniques are very helpful to place the bone
flap precisely over the tumor. Because most of the patients will receive
postoperative radiotherapy, a linear scalp incision is preferred to decrease
the chance of complications caused by poor wound healing. To lessen the
possibility of a postoperative deficit, stereotactic or intraoperative
ultrasound techniques should be used to locate small subcortical tumors
precisely before making any cortical incision. Intraoperative ultrasound or
direct localization of the lesion with the stereotactic probe or needle
should be used during exposure of the lesion through a small cortical
incision; these techniques provide a direct route to the tumor and a means
of avoiding eloquent areas of the brain. These measures prevent the
prolonged exploration for an elusive small lesion, which is the major cause
of postoperative neurological deficits. Meticulous haemostasis is critical
for preserving visualization in the plane of demarcation between tumor and
compressed or oedematous normal brain. Self-retaining brain retractors should
be used to minimize the manipulation of tissues necessary for exposing the
tumor.
Microsurgical, laser, and
ultrasonic aspiration techniques are invaluable adjuncts to localizing devices
for the safe removal of small metastatic lesions that are deep-seated or
adjacent to eloquent areas of the brain. Complication rates of less than 5
percent are reported in recent series. Very small lesions « 1 cm in diameter)
are better localized stereotactically than with ultrasound. Subcortical tumors
should be approached by a dissection plane through the sulcus. An approach
through the sylvian fissure is often preferred for tumors deep and medial to the
middle cerebral artery. Only the most superficial tumors should be removed
through an opening in the gyrus. When the lesion is in the speech area, consideration
should be given to performing the surgery with the patient awake, using cortical
mapping and cortical stimulation to identify speech and motor areas. If the
decision is made to remove a deeply located lesion, stereotactic localization
and careful planning of the surgical approach are essential. For deep midline
lesions, a computer-assisted system is helpful in planning trajectory so as to
avoid important vascular and neural structures.
Every effort should be made to
excise the lesion completely, because complete removal seems to be related to
both the length and the quality of postoperative survival. Metastatic
lesions are usually very well circumscribed; in most cases, therefore, complete
excision should be achievable. Some series report that complete excision is
obtained in only about two-thirds of cases. Other series show that
complete excision is possible in almost 100 percent of cases, as judged by early
postoperative CT scanning or MRI. If there is any question of residual
metastatic tumor at the end of the resection, a frozen section analysis of the
tumor bed should be performed so that an intraoperative decision can be made
about the completeness of the resection. Complete resection with tumor-free
margins should be attempted rigorously by using the above-mentioned techniques,
including microscopic visualization of the tumor bed. However, recurrences will
occasionally result even when intraoperative tumor margin biopsies are negative
and postoperative CT scanning or MRI shows no residual tumor.
Recurrent Metastases
Complete tumor resection is
accomplished in about two-thirds of cases. In one randomized study,49
contrast CT scans done 1 to 5 days postoperatively showed removal in all cases.
However, late local recurrence appeared in 20 percent of these patients. The
potential for late local recurrence is the basis for administering radiotherapy
after surgical resection. Kelly et al reported no local recurrences in their
series of 44 patients using very sophisticated computer-assisted stereotactic
resection techniques. They pointed out, however, that the postoperative
radiotherapy that most of their patients received may have contributed to their
excellent results. On the basis of currently available data, postoperative
radiation should be administered even after apparently "complete" surgical
resection.
Commonly, patients with
recurrences have already been treated with radiotherapy to the brain, which
limits the amount of subsequent radiation that can be given safely. Several
uncontrolled studies have found no meaningful increase in survival or control
of neurological symptoms in patients who underwent further radiotherapy after
the recurrence of brain metastases. Conventional surgery for recurrent
tumors is an option for patients who have a single recurrence and controlled
systemic disease. Sundaresan et al. reported a series of 21 patients who were
treated with craniotomy for the initial brain lesion and who underwent a second
craniotomy for recurrence. After the second operation, two-thirds of the
patients experienced neurological improvement, and the median survival time
after operation for the recurrence was 9 months. If the lesion is presumed to be
radioresistant (such as a metastasis of kidney, melanoma, or lung origin), and
the recurrent lesion remains a single metastasis, repeat surgical resection is
the best option when the patient's Karnofsky rating is > 60 percent and the
systemic disease is controlled. The efficacy of interstitial brachytherapy in
this circumstance is being determined in clinical trials.
Stereotactic radiosurgery has
been used to treat recurrent brain metastases. Radiosurgery has the theoretical
advantage of being able to deliver large doses of additional radiation to small
areas of the brain, Further studies are needed to determine the true value of
stereotactic radiosurgery in the management of recurrent brain metastases.
Multiple Lesions
The value of surgery in the
management of multiple metastases remains to be demonstrated. Two published
retrospective studies reached opposite conclusions regarding the safety and
efficacy of surgical removal of more than one brain metastasis. Bindal et
al. compared patients with multiple metastases who underwent resection of all
of their brain metastases to patients with multiple metastases who underwent
resection of some but not all of their brain tumors. A further comparison was
made with patients with single metastases who were treated with complete
resection plus WBRT. The authors found that the group with completely resected
multiple metastases did relatively well (median survival 14 months); their
survival rates were similar to those of the group treated by resection of a
single metastasis (median survival 15 months). The patients who did not undergo
excision of all of their brain tumors did less well (median survival 6 months).
Hazuka et al. reported a retrospective surgical series containing 18
patients with multiple metastases and 28 patients with single metastases. The
group with multiple metastases had a median survival of 5 months; those with
single metastases had a median survival of 12 months.
Current standard practice is to
treat multiple metastases with WBRT alone. It is logical to operate on patients
with multiple metastases who have one life-threatening brain lesion. The intent
of surgery in these cases is to remove the single life-threatening lesion
without removing the other lesions. Additionally, resect a
lesion too large to be treated with radiosurgery (diameter> 3.5 cm) when other
lesions can be treated by radiosurgery.
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