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Chapter 16
Brain Metastases
Abstract
Brain metastases deeply affect survival and quality of life in patients with cancer.
Actually the management of brain metastases are guided by prognostic factors,
including the Karnofsky Performance Status, tumor histology, number of metastases,
patient age, and status of systemic disease.
The treatment options for the most of brain metastases are radiosurgery (RSR),
computer-assisted surgery, or whole brain radiation therapy (WBRT).
Impressive advances in neuronavigation have conduct to neurosurgical removal of
metastases safer, even in eloquent areas of the brain.
Impressive technology advances also enhances the efficacy and safety of conformal
radiosurgery planning using various modern stereotactic radiosurgery (SRS),
including newer frameless-based systems.
However even with these advances, controversialstill remains on whether should
defer whole brain radiotherapy (WBRT) in patients undergoing SRS or surgery and
when to use SRS “boost” in a patient undergoing WBRT.
Introduction
Brain metastases represent an important cause of morbidity and mortality, and are the
most common intracranial tumors in adults, occurring in approximately 10% to 30% of adult
cancer patients. The risk of developing brain metastases varies according to primary tumor
type, 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 most widely used treatment for patients with
multiple brain metastases is whole brain radiotherapy. In this chapter we will discuss different
aspects related to the diagnosis, treatment and radiotherapy techniques for treating brain
metastases.
Gustavo Arruda Viani
242
1. Epidemiology
• Brain metastasis are considered the most common intracranial tumors.
• Brain metastasis has about to 200,000 cases per year in the USA.
• It is estimated that up to 40% of all cancer patients will develop brain metastases.
• The most common primary tumors metastasizing to the brain includes lung, breast,
melanoma, renal, and colon.
• Brain metastasis from renal cell, choriocarcinoma, and melanoma has a higher risk of
hemorrhagic event.
• An improved detection by magnetic resonance imaging (MRI) and a better control of
extracerebral disease due to improved systemic therapy, can be related with an
increase in the incidence of brain metastases.
References
Johnson JD, Young B. Demographics of brain metastasis. Neurosurg Clin N Am. 1996;7
(3):337.
2. Pathology
To achieve the brain, the cancer cell must develop its own blood supply, invade local
tissues, and enter the circulation either by invading venules or lymph channels that eventually
reach the venous circulation, following to the heart and after to the brain.
The cancer cell attaches to the endothelial surface, induces endothelial retraction,
migrates through the breach, dissects beneath the endothelium, degrades the vascular
basement membrane, and migrates out of the vascular compartment to form a metastatic
tumor (figure-1).
Figure 1. Pathological aspect of Brain metastases of lung cancer.
Brain Metastases
243
Symptoms
Description
Headache
Headaches occur in approximately 40 to 50 % of patients with brain metastases.
Multiple lesions are associated with more symptoms thatn single lesion.
The classic early morning headache is uncommon, it is highly suggestive. nausea
and vomiting are suggestives of a possible brain tumor, mainly in patients with a
change of prior headache pattern, and with abnormal neurologic examination.
Focal
dysfunction
20 to 40 % of patients have a focal neurologic dysfunction as a presenting
symptom. Hemiparesis is the most common complaint.
Seizures
10-20 % of patients have seizures as the presenting symptom. Seizures in patients
with brain metastases are almost exclusively associated with supratentorial disease.
Cognitive
dysfunction
Cognitive dysfunction, including memory problems and mood or personality
changes, is the presenting problem in about 35 % of cases.
Stroke
5- 10 % of patients have strokes. Hemorrhage caused by metastasis bleeding,
hypercoagulability, invasion or compression of an artery by tumor.
Reference
Lassman AB, DeAngelis LM. Brain metastases. Neurol Clin. 2003;21(1):1
3. Clinical Features
Brain metastase has a varied clinical features and any cancer patient who develops
neurologic symptoms or behavioral abnormalities should be investigated to exclude it. Table1 sumarizes the main symptoms related with brain metastases.
Table 1. Symptoms and signs of brain metastases
Reference
Lassman AB, DeAngelis LM. Brain metastases. Neurol Clin. 2003;21(1):1
4. Diagnosis and Evaluation
• Any cancer patient who develops neurologic symptoms or behavioral abnormalities
should be investigated to exclude brain metastases.
• However, there are some differential diagnosis such as; primary brain tumors,
infectious processes, progressive multifocal leukoencephalopathy, demyelination,
cerebral infarction or bleeding and radiation necrosis that should be considered.
• Imaging studies provide useful information but brain biopsy is necessary in some
cases for a definitive diagnosis. Other important diagnostic issues include determining the number and location of metastases and the evaluation of the patient
without a known primary tumor.
• Contrast-enhanced MRI is the standard imaging study to detect brain metastases
(figure-xx). Contrast-enhanced MRI is more sensitive than either nonenhanced MRI
Gustavo Arruda Viani
244
or CT scanning for patients suspected of having cerebral metastases and it is helpfull
in differentiating metastases from other central nervous system (CNS) lesions
• Radiographic characteristics that can help differentiate brain metastases from other
CNS lesions are: the presence of multiple lesions, localization at the junction of the
grey and white matter, circumscribed margins and large amounts of vasogenic edema
(figure-2).
Figure 2. Brain MRI showing aspects for brain metastases.
References
Sze G, Milano E, Johnson C, Heier L. Detection of brain metastases: comparison of contrast-
enhanced MR with unenhanced MR and enhanced CT. AJNR Am J Neuroradiol.
1990;11(4):785.
Schaefer PW, Budzik RF Jr, Gonzalez RG. Imaging of cerebral metastases. Neurosurg Clin N
Am. 1996;7(3):393.
5. Prognostic Factors
• There are many prognostic factors associated with overall survival for patients with
brain metastases.
• Among these prognostic factors the most important are: Performance status (major
determinant of survival: the Karnofsky performance status [KPS] score), age, number
of brain metastases (single versus multiple), primary tumor type (lymphoma, germ
cell, and breast versus other), systemic tumor activity (controlled versus uncontrolled), and time to develop brain metastases.
• Actually there are two prognostic index used to guide the choice of treatment for
patients with brain metastases. The Recursive Partitioning Analysis (RPA) is the first
effective predictive tool studied in patients pooled from three Radiation Therapy and
Brain Metastases
245
Class
Prognostic factors
Median survival, months
I
KPS ≥70 percent
7.1
Age <65 years
Controlled primary site
No extracranial metastases
III
KPS <70
2.3
II
All others
4.2
Oncology Group (RTOG) trials. The Graded Prognostic Assessment (GPA) is the
newest quantitative index based on RTOG databases Table-2.
Table 2. Recursive partitioning analysis
Reference
Gaspar L, Scott C, Rotman M, Asbell S et al. Recursive partitioning analysis (RPA) of
prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases
trials. Int J Radiat Oncol Biol Phys. 1997;37(4):745.
6. Treatment
• The goal of initial treatment of patients with brain metastasis is to stabilize the CNS
symptoms.
• Surgical decompression may be a priority for patients who presenting with
significant midline brain shift, intratumoral or intracerebral hemorrhage, or massive
brain edema.
• Anticonvulsants should be administered only to patients at risk for seizure, and use
should be minimized to single therapy at the lowest effective dose.
• The perilesional vasogenic edema common with brain metastases responds to oral
glucocorticoid steroids. Recommended dosages of dexamethasone vary significantly
between 4 and 16 mg/d. The steroid dose should be tapered as quickly as possible to
reduce adverse effects.
• Optimal treatment for a patient with brain metastases must be individualized based
on prognostic factors, patient preference, status of systemic disease, and expertise
available at the treating center.
• Large randomized trials evaluating prognostic factors of patients with brain
metastases has found that the factors associated with prolonged survival include; a
Karnofsky performance status of 70 or more, age less than 60 years, and with a
controlled primary tumor with the brain as the sole site of metastases.
• For patients with all or most of these characteristics, an aggressive treatment with
surgical resection or SRS to eradicate brain metastases is recommended.
Gustavo Arruda Viani
246
Surgery and WBRT vs WBRT
Patchell et al
(1990)
48 patients with a single brain metastasis were randomized to surgical removal of the
brain tumor followed by WBRT (surgical group) or needle biopsy and WBRT
(radiation group).
25patients in the surgical group and 23 in the radiation group) formed the study group;
Recurrence was less frequent in the surgical group than in the radiation group (20
%vs. 52% P < 0.02).
The overall length of survival was significantly longer in the surgical group (p=0.01),
and the patients treated with surgery remained functionally independent longer
(p=0.005).
Vecth et al.
(1993)
63 patients with a single brain metastase was randomized to WBRT plus surgery or
WBRT.
The combined treatment compared with WBRT led to a longer survival (p = 0.04).
Patients with progressive extracranial cancer had a median overall survival of 5
months and a FIS of 2.5 months irrespective of given treatment.
Improvement in functional status occurred more rapidly and for longer periods of time
after neurosurgical excision and radiotherapy than after radiotherapy alone.
Figure 3. Kaplan meier survival curve of patients with brain metastases treated with whole brain
radiotherapy. KPS > 70 and patients submmited to surgical resection had better survival in a
retrospective review of 270 patients.
• Neurosurgical resection is suggested for a single or limited number of metastases in a
surgically accessible location , whereas SRS is indicated for patients with a limited
number of lesions, surgically inaccessible locations, or for those who are not surgical
candidates.
• For patients with multiple brain metastases who are not candidates for either surgical
resection or SRS, we suggest WBRT.
• For patients initially managed with either surgical resection or SRS, we suggest
WBRT following surgery or SRS to reduce the incidence of local recurrence and new
brain metastases, although this is not associated with an increase in survival and may
be deferred in selected patients (table-3).
Table 3. Clinical evidence for WBRT plus surgery, SRS plus WBRT and WBRT
alone in patients with brain metastases
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247
Surgery or SRS and WBRT vs Surgery or SRS
Patients with 1-3 brain metastases of solid tumors and WHO performance status (PS)
of 0 to 2 were treated with complete surgery or SRS and randomly assigned to
adjuvant WBRT (30 Gy in 10 fractions) or observation (OBS).
Of 359 patients, 199 underwent SRS, and 160 underwent surgery. In the SRS group,
100 patients were allocated to OBS, and 99 were allocated to WBRT. After surgery,
79 patients were allocated to OBS, and 81 were allocated to adjuvant WBRT.
Overall survival was similar in the WBRT and OBS arms (P = .89). WBRT reduced
the 2-year relapse rate both at initial sites (surgery: P<.001; SRS: P = .040) and at new
sites (surgery: 42% to 23%, P = .008; SRS: 48% to 33%, P = .023).
Intracranial progression caused death in 78 (44%) of 179 patients in the OBS arm and
in 50 (28%) of 180 patients in the WBRT arm.
SRS plus WBRT vs WBRT
Andrew et al.
(2004)
Patients with 1-3 newly diagnosed brain metastases were randomized to WBRT or
WBRT followed by SRS.
333 patients were assigned WBRT and SRS and 164 were allocated WBRT alone.
Univariate analysis showed that there was a survival advantage in the WBRT and SRS
for patients with a single brain metastasis (p=0.0393). Patients in the SRS group were
more likely to have a stable or improved Karnofsky Performance Status (KPS) score at
6 months' follow-up than were patients allocated WBRT alone (43% vs 27%,
respectively; p=0.03).
References
Patchell RA, Tibbs PA, Walsh JW, et al. A Randomized Trial of Surgery in the Treatment of
Single Metastases to the Brain. N Engl J Med 1990;322:494-500.
Kocher M, Soffietti R, Abacioglu U et al. Adjuvant whole-brain radiotherapy versus
observation after radiosurgery or surgical resection of one to three cerebral metastases:
results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29(2):134.
Vecht CJ, Haaxma-Reiche H, Noordijk EM et al. Treatment of single brain metastasis:
radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33(6):583.
Andrews DW, Scott CB, Sperduto PW, et al. Whole Brain Radiation Therapy with or without
Stereotactic Radiosurgery Boost for Patients with One to Three Brain Metastases: Phase
III Results of the RTOG 9508 Randomised Trial. Lancet 2004;363:1665-1672.
7. Radiotherapy Technique
The patient lies supine in a thermoplastic maskl with the neck in a comfortable neutral
position. The planning can be done with conventional simulator or CT simulator. CT
simulator is preferable only if focal external beam radiotherapy is given after surgical
resection. After acquired the slices from the skull top to the larynx, the borders of treatment
volumes can be limited (Figure-4). If whole brain irradiation is given, beams are defined in
the simulator to cover the whole skull from vertex to a line joining the external auditory
meatus with the outer canthus of the orbit. If there is any evidence of involvement of the skull
base this line will need to be 1–2 cm lower to ensure tumour is included in the treatment
volume.
Gustavo Arruda Viani
248
Figure 4. WBRT fields. (a) 3D-CRT (b) conventional radiotherapy.
Simple opposing lateral beam arrangements are used for whole brain irradiation with
wedging if necessary to improve dose distribution (figure-5). For focal treatment, plans are
drawn up after CT scanning for optimal dose to tumour and minimal dose to normal tissues,
often using non-coplanar arrangements. Typical fractionation schemes used in clinical
practice include 4 Gy × 5, 3 Gy × 10, 2.5 Gy × 15, and 2 Gy × 20. All schemes with
comparable results.
Figure 5. WBRT for brain metastases.
SRS delivers single or very limited number of high doses to a discrete treatment volume
by using multiple convergent beams. This results in a rapid fall-off of dose at the edge of the
target volume and a clinically insignificant dose to adjacent normal tissue (figure-6).
An increasing number of studies have suggested that SRS is at least as effective as
surgery for the treatment of brain metastases in selected patients. The efficacy of SRS is
independent of the primary tumor type, but is influenced by the dose of radiation and the
tumor volume. Actually a minimum dose of 14 Gy is recommended. However large lesions
need to be treat with lower doses due to neurotoxicity. Maximum tolerated dose for single
fraction radiosurgery: tumor diameter < 20 mm, dose 24 Gy; diameter 21–30 mm, dose 18
Gy; diameter 31–40 mm, dose 15 Gy.
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249
Neurologic symptoms from SRS may be due to transient swelling that begins 12 to 48
hours after therapy. Symptoms can include mild nausea, dizziness or vertigo, seizures, or new
headache. A short course of steroids around the time of radiosurgery may be useful to prevent
or minimize acute SRS-related toxicity.
Figure 6. Isodoses distribution and treatment planning simulation and treatment with Linac SRS.
Conclusion
• Radiation therapy plays an pivotal role in the palliative treatment of brain metastasis.
• Whole brain irradiation following surgical resection (or stereotactic radiosurgery) is
considered the standard treatment for solitary brain metastasis.
• Whole-brain irradiation with or without stereotactic radiosurgery is the choice of
treatment for palliation in patients with more than one intracranial metastatic lesions.
• Stereotactic radiosurgery alone for 4 or fewer brain metastases is also a reasonable
option in highly selected patients.
