Brain Metastases: Old Problem, New Strategies

Hematol Oncol Clin N Am 21 (2007) 369–388

HEMATOLOGY/ONCOLOGY CLINICSOF NORTH AMERICA

Brain Metastases: Old Problem,New Strategies

Teri D. Nguyen, MD, Lauren E. Abrey, MD*Department of Neurology, Memorial Sloan-Kettering Cancer Center,1275 York Avenue, New York, NY 10021, USA

Brain metastases are a common complication of breast cancer and can befound in 20% to 30% of patients at autopsy [1–3]. Clinically evidentbrain metastases occur in 10% to 15% of patients [3–5]. Central nervous

system (CNS) dissemination is distinguished from other sites of advanced dis-ease by conferring a unique morbidity and altering subsequent management ofthe patient’s disease. Morbidity from neurologic disability significantly affectsquality of life, and interruption of systemic treatment often is needed to addressmore urgent neurologic presentations. When left untreated, peritumoral edemaleads to progressive neurologic deterioration and death secondary to increasedintracranial pressure in about 1 to 2 months [6,7]. Avoiding or delaying this faterequires a working knowledge of supportive and definitive treatments for brainmetastases. Data from studies that include other solid tumor histologies pro-vide the bulk of supporting evidence for the use of therapies, such as steroids,antiepileptic drugs (AEDs), surgery, and radiation. However, there are severalissues specific to brain metastases from breast cancer, illustrating that this dis-ease should be considered pathophysiologically distinct, and future researchshould be tailored accordingly.

DIAGNOSISPatients who present clinically with brain metastases can have signs of in-creased intracranial pressure (headache, nausea, and vomiting), mental statuschanges, seizures, or focal signs. Focal signs are most frequently described asmotor paresis, which may in part reflect the relative ease of identifying this par-ticular deficit on a cursory neurologic examination (Table 1). Leptomeningealcarcinomatosis can present similarly, except that focal signs are more often ex-hibited by cranial nerve abnormalities and can have a multifocal distributionindicating the widespread process. Vertebral body metastases, although notconsidered CNS disease, can extend into the epidural space and cause spinalcord compression syndromes presenting with back pain, gait impairment,

*Corresponding author. E-mail address: [email protected] (L.E. Abrey).

0889-8588/07/$ – see front matter ª 2007 Published by Elsevier Inc.doi:10.1016/j.hoc.2007.03.009 hemonc.theclinics.com

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and myelopathy. Bulky, nodular leptomeningeal disease can extend into thespinal cord and also cause myelopathy. Intraparenchymal spinal metastasesare rare.

New neurologic symptoms prompt evaluation with imaging. In the acutepresentation (rapid change in examination within 24 hours), a CT without con-trast of the brain is appropriate to quickly identify life-threatening pathologies,such as large parenchymal or subarachnoid hemorrhage, acute hydrocephalus,and impending herniation from tumor or edema mass effect. In a potentiallyunstable patient, MRI is actually an inappropriate study because it can takemore than half an hour to complete leaving the patient unmonitored for an un-acceptably long period of time. Some lesions may appear hyperdense on non-contrast CT because of acute intratumoral hemorrhage or from increasedtissue density of the tumor itself. Lesions typically have an impaired blood–brain barrier and are best distinguished using contrast-enhanced CT orMRI, with MRI being a significantly more sensitive modality (Fig. 1) [8].MRI also has the ability to help differentiate the lesion from other potential di-agnoses, such as stroke. Leptomeningeal disease and posterior fossa disease arealso better imaged with contrast-enhanced MRI. Even in the absence of typicalgadolinium enhancement on the surface of brain structures, subtle fluid atten-uated inversion recovery signal hyperintensity of superficial brain tissue can bea sensitive indicator of leptomeningeal disease. CT of the brain can have signif-icant beam-hardening artifact from the skull that is most severe in the posteriorfossa, making smaller cerebellar lesions difficult to diagnose, even with the ad-ministration of contrast.

In a patient who has widespread systemic disease, multiple intracranial le-sions distributed classically at the corticomedullary junction leave little doubtas to the diagnosis. Immunosuppressed or septic patients may develop brainabscesses that can have a similar appearance and distribution. Single or solitarybrain lesions are even more difficult to define because primary brain tumors

Table 1Presenting clinical features in 1013 patients who had brain metastases

Signs and symptoms Prevalence of feature (%)

Cognitive or mental status change 34Headache 31Weakness 24Seizures 19Ataxia 11Visual change 5Nausea or vomiting 4Sensory change 2Papilledema 0.5Other 4None of the above 9

371BRAIN METASTASES: OLD PROBLEM, NEW STRATEGIES

can occur in patients who have systemic malignancies. About 3% of patientswho had high-grade glioma were found to have a second malignancy in oneretrospective study [9]. Patients may also have a history of more than one ac-tive systemic malignancy. Distinguishing which cancer has metastasized to thebrain cannot be seen from imaging alone and requires surgical resection to ac-quire pathology. In one prospective study of surgery for brain metastases, 11%of histologically proven primary malignancies sent for resection of a brain me-tastasis were diagnosed as either a second malignancy or an infectious orinflammatory disease [10].

Suspected leptomeningeal disease requires either radiographic confirmationwith contrast-enhanced MRI or positive cytology from spinal fluid analysis.The sensitivity of both methods is about 75%, but serial lumbar puncturescan increase the sensitivity to more than 90% with the third sample [11,12].Specificity of cytology (100%) is also superior to MRI, in which false positivesmay result from infectious or inflammatory disease. Artifactual dural enhance-ment from intracranial hypotension can be caused by a lumbar puncture. Neu-roimaging should therefore precede cerebrospinal fluid (CSF) sampling.Evidence of disease in the spine should prompt imaging of the brain becausethere is likely to be concomitant disease. This imaging also allows an assess-ment of safety before performing a diagnostic lumbar puncture in a patientwho has potentially increased intracranial pressure at risk for herniation. Paren-chymal disease found in the brain does not mandate spine imaging unless thepatient has symptoms or signs that localize to the spine. If leptomeningeal dis-ease is seen in the brain, however, neuro-axis screening is appropriate to

Fig. 1. Superior resolution of MRI for brain metastases. (A) Gadolinium-enhanced T1weighted MRI of brain metastases in the posterior fossa. (B) Noncontrast CT of same patientwith hyperdense lesions, some obscured by beam-hardening artifact of the skull.

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identify bulky spinal disease that may require radiation or complicate treatmentwith intended intrathecal chemotherapy.

OCCULT BRAIN METASTASESOf growing interest and frequency is the acquisition of brain imaging as surveil-lance for brain metastases before starting chemotherapy in the absence of a clin-ically symptomatic indication for the study. In some instances, asymptomaticpatients are screened for brain lesions to qualify for enrollment into a clinicalstudy. Most therapeutic trials exclude patients who have CNS involvement be-cause it usually carries a poor prognosis. Certain investigational agents mayhave a theoretic increased risk for hemorrhage, such as many of the new angio-genesis inhibitors. In some cases, screening is merely a function of the ease andavailability of MRI imaging at certain institutions (or is motivated by patientrequest).

The diagnosis of occult brain metastases poses a therapeutic dilemma be-cause there are few data to guide appropriate management of these lesions.One study by Miller and colleagues [13] retrospectively reviewed 155 screeningbrain CTs and MRIs obtained before enrollment into four separate therapeuticclinical trials for breast cancer that required exclusion of CNS disease. Twenty-three patients (14.8%) were reported to have occult CNS metastases, compara-ble to other studies reporting occult brain metastases in breast cancer patientswith a range of 14% to 20% [3,4,14]. This cohort was compared with a group ofsymptomatic patients referred for whole-brain radiation therapy (WBRT) dur-ing the same time period. The authors demonstrated that CNS dissemination,whether occult or symptomatic, conferred a poorer prognosis. In addition,patients who had occult brain metastases had similar survival to symptomaticpatients. Both groups had the same underlying disease (merely detected at dif-ferent points in time), and most were treated with WBRT. This study begsthe question of whether treating occult lesions at diagnosis, with WBRT orother definitive treatment modalities, is appropriate or necessary. Perhaps de-ferring treatment until the time of radiographic or clinical progression is equiv-alent in efficacy, delays radiation toxicity, and allows more flexibility in offeringsystemic regimens.

RISK FACTORS FOR BRAIN METASTASESFROM BREAST CANCERTarget organ and tumor cell–specific factors interact to mediate viable distantmetastases. Many such factors have been identified in association with the de-velopment of brain metastases from breast cancer, mostly by way of retrospec-tive studies (Box 1). Unfortunately, there are often multiple confoundingfactors making an attributable risk from any one factor difficult to discern.Risk factors for brain metastases from breast cancer can be categorized intotwo domains: those related to having advanced disease, and intrinsic tumorsignatures that seem to confer tropism for CNS metastasis.


Advanced DiseaseBrain metastases are typically a late complication of disease from breast cancer.Patients presenting with stage III disease are 1.5 times more likely to developCNS metastases than those presenting with early-stage disease [15]. The brainis the initial site of relapse in less than 5% of patients [16–18]. A single braintumor is less likely to be an isolated site of distant disease for breast cancerthan for other solid tumors, such as lung, melanoma, or renal cell carcinoma.The median time from original diagnosis of breast cancer to the developmentof brain metastases is 2 to 3 years, and brain metastases lag systemic metastasesin presentation by 6 to 13 months [19,20]. Young age or menopausal status hasbeen shown in several studies to be significantly correlated with the develop-ment of brain metastases from breast cancer [3,15,19,21]. Other studies havenot corroborated this association, however, and some of the effect is attributedto longer survival of younger patients [20,22]. Younger age or premenopausalstatus has also been correlated with estrogen receptor negative (ER�) tumors,which may be confounding [23].

Longer survival and subsequent increased risk for reaching advanced diseasewith lung involvement may be the underlying mechanism for many brain me-tastases from breast cancer. Few studies assessing risk factors look specificallyat concomitant lung disease; those that do show a striking correlation. In a mul-tivariate analysis of 215 patients who had early-stage breast cancer, lung metas-tases as an initial site of relapse conferred a hazard ratio of 4.3 (P ¼ .0003) forsubsequent brain metastases [20]. In this study, other variables associated withadvanced disease were not predictive of brain metastases in the univariate anal-ysis, including tumor size, lymph node involvement, and the presence of livermetastases. Vascular anatomy allows pulmonary tumors a gateway into thebrain. Patients who present with brain lesions without first developing diseasein the lung are a small population that merits further study.

Box 1: Risk factors for brain metastases from breast cancer

Advanced disease/longer survival

Young age

Tumor size

Node status

Lung metastases

Adjuvant hormone and chemotherapy

Tumor signatures

Histology

Grade

ER�/PR�HER-2+

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Increased risk for isolated progression of brain metastases has been describedin studies of patients receiving adjuvant chemotherapy. In part, the effect maybe secondary to improved survival in these patients. More specifically, theblood-brain barrier is believed to provide sanctuary for tumor cells that havemetastasized to the brain, allowing them to flourish later even in the settingof stable systemic response. This result was seen in several studies of patientswho had advanced breast cancer. Six of 52 (12%) patients treated with pacli-taxel, and 11 of 58 (19%) patients treated with epirubicin and docetaxel, hadisolated progression of disease in the CNS after initial systemic response totreatment [24,25]. In the combination therapy study, 30% of treated patients de-veloped symptomatic brain metastases. In 39% of those patients, the brain wasthe only site of progression. These rates were higher than expected, even forthe advanced-stage population. Critics of this ‘‘sanctuary’’ theory point outthat brain metastases large enough to require angiogenesis for growth arenot protected by a normal blood–brain barrier and should be equally as re-sponsive to chemotherapy as their systemic counterparts. Possibly, exposureto adjuvant therapy selects for survival of treatment-resistant cells that then es-tablish themselves in the CNS. Tissue correlates of differences in tumor biologyby metastatic site are needed to better answer this question.

Tumor SignaturesSeveral studies have correlated histologic subtypes of breast cancer to particularpatterns of dissemination, implying discrete tumor and target organ interac-tions. Infiltrating ductal carcinoma (IDC) more often spreads to the lung,whereas infiltrating lobular carcinoma (ILC) is associated with more boneand visceral disease [26–28]. In one of these studies, 1391 records of patientswho had histologically confirmed breast cancer were reviewed; there was a sta-tistically significant increased incidence of brain and lung metastases in patientswho had IDC compared with patients who had ILC. Conversely, ILC wasmore often associated with peritoneal metastases. Potential confounders werecomorbid lung disease and age; patients who had IDC were slightly younger(54.3 years versus 56.3 years, P ¼ .02). Hormone receptor status was wellmatched between the two groups, although about 10% to 15% of records didnot have this information available [28]. In a separate study of 2257 operablebreast cancer cases, IDC histology was significantly associated with estrogenreceptor positive/progesterone receptor positive (ERþ/PRþ) tumors, in whicha lower risk for CNS disease would be expected. Unfortunately, the correlationwith brain metastases was not analyzed. Conversely, there is some evidencethat ILC histology confers higher risk specifically for leptomeningeal carcino-matosis [29].

High-grade histology has also been believed to confer a greater propensityfor metastasis [19,30]. An interesting example of this was demonstrated ina study by Tsuda and colleagues [31], in which they correlated myoepithelialimmunophenotype with the development of brain metastases. High-gradeIDCs can have large, acellular zones within them that are highly correlated


with the myoepithelial phenotype. Patients who have this feature on pathologyin greater than 30% of the original tumor specimen had an increased relativerisk for developing brain (3.77, P ¼ .03) and lung (3.67, P ¼ .008) metastases.Preferential spread to the brain from higher-grade tumor is hard to separatefrom tropism for lung tissue and not corroborated by some other studies[19,22].

A variable that may truly be an independent risk factor for brain metastasesfrom breast cancer is hormone receptor status. Significant evidence supportsthe predictive value of tumor hormone receptor status for particular patternsof metastatic disease. Several studies have shown a correlation betweenER�/PR� pathology to the development of brain and visceral metastases. Incontrast, patients who have ERþ/PRþ breast cancer tend to develop bone me-tastases often exclusive of CNS disease [23,32,33]. Slimane and colleagues [20]analyzed data from 215 patients who had metastatic breast cancer in whom riskfactors for brain metastases identified in a multivariate analysis were re-evalu-ated in a confirmatory series of 199 patients. Negative hormone receptor statushad a hazard ratio of 4.2 (P ¼ .002). The only other variables found to be sig-nificant were lung metastases as site of first relapse, and a metastasis-free inter-val of 24 months or more. In a larger multivariate analysis by Tham andcolleagues [34], ER� tumor had a hazard ratio of 2.8 (P < .001) for thedevelopment of CNS metastases. Other factors also found to be significantwere young age, IDC histology, and larger tumor size. A separate study by Pes-talozzi and colleagues [30] reviewed records of 9524 patients who had earlybreast cancer who enrolled in International Breast Cancer Study Group trialsbetween 1978 and 1999. They looked for factors predictive of the CNS as firstsite of recurrence, and identified the following: node-positive disease, ER�tumors, tumor size greater than 2 cm, tumor grade 3, age less than 35 years,and HER-2þ tumors. Not only was the measure specific to CNS disease, butthe effects of taxane and trastuzumab therapy are minimized as they werenot widely used during the treatment timeframes.

Speculation as to whether trastuzumab was facilitating CNS disseminationstemmed from observations that 30% to 48% of patients treated with trastuzu-mab develop brain metastases [35–37]. Lai and colleagues [36] compared 79 pa-tients treated with trastuzumab with 264 patients who did not receivetrastuzumab, all of whom were well matched for variables, such as hormonereceptor status, age, grade, node status, tumor size, and presence of lung metas-tases. There was no significant difference in incidence of CNS dissemination.The groups did differ in HER-2 status and the presence of visceral metastases.Although this seems to indicate that tumor biology and advanced disease aremore significant than the treatment, the authors concluded that HER-2 statuswas not predictive of CNS metastases. Stemmler and colleagues [35] reviewed136 patients who had overexpression of HER-2 who were treated with trastu-zumab and found that hormone receptor status was predictive of brain metas-tases in this group and may be a confounding factor in this population. Datafrom patients who are HER-2–positive randomized to receive trastuzumab or

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other treatments at initial diagnosis of stage IV disease are not available at thistime.

Until recently, large studies with multivariate analyses of risk factors forbrain metastases from breast cancer have not included HER-2 status. A largereview of 2685 patients who had metastatic breast cancer was performed inwhich the multivariate analysis identified ER� tumor, IDC histology, andyoung age as independent risk factors for developing CNS metastases. HER-2overexpression was not a significant risk factor, except for those patients whodeveloped CNS metastases as their first site of relapse. These patients alsohad decreased overall survival [34]. A similar result was found in a study bySouglakos and colleagues [38] of 492 breast cancer patients who had both early-and advanced-stage disease. In this study, however, HER-2 status was a signi-ficant risk factor in the univariate analyses for all CNS metastases, along withmenopausal status, presence of visceral disease, and CK-19 mRNA-positivecirculating tumor cells.

The sanctuary theory is believed to best explain the high incidence of brainmetastases in these patients. Trastuzumab is a monoclonal antibody directedagainst the epidermal growth factor receptor family tyrosine kinase HER-2,overexpressed in about 25% to 30% of breast cancers and believed to confera poorer prognosis [39,40]. The agent is a large protein (148 kD) that doesnot cross the blood–brain barrier and achieves levels in the CSF 200-foldless than serum concentrations [41]. Among patients treated with trastuzumabwho develop brain metastases, 48% to 52% have stable or responsive systemicdisease at the time of CNS progression. This finding translates to isolated CNSprogression in about 15% to 18% of patients [35,37,42]. Inability to treat reser-voirs of disease in the CNS is a limitation of the drug’s efficacy. Ironically, useof trastuzumab has had significant survival benefit for this targeted populationof patients leading to longer survival of patients who have advanced diseaseand subsequent increased risk for brain metastases. Patients treated with tras-tuzumab developed CNS dissemination 14 to 16 months after initial relapse,which is a slightly longer interval than historical controls [35,37].

One should be cautious in concluding that these patients have an abnormallyhigh rate of brain metastases. Autopsy studies have estimated the lifetime prev-alence of brain metastases in breast cancer patients to be near 30%. Most ofthese autopsy studies were done several decades ago when survival from sys-temic disease was shorter. With larger numbers of patients living with pro-longed advanced disease, and detection methods improving in quality andfrequency, the higher rates of CNS metastasis seen today seem understandable.

SUPPORTIVE TREATMENTS FOR CENTRAL NERVOUS SYSTEMMETASTASES FROM BREAST CANCERManagement of a patient who has CNS metastases is composed of symptom-atic and definitive therapies. The mainstays of symptomatic control are steroidsfor tumor-related edema, AEDs for seizure control, and multidisciplinary inter-ventions aimed at minimizing neurologic disability.


Steroids stabilize the integrity of tumor vasculature that has increased perme-ability relative to the normal blood–brain barrier. Decreasing intracerebralpressure can alleviate symptoms within hours of steroid administration. Itcan also allow better penetration of chemotherapeutic agents that rely on hy-drostatic pressures to penetrate brain parenchyma. Dexamethasone is preferredfor its low mineralocorticoid activity. Pharmacokinetics of the drug permittwice daily dosing, which is optimal for patients because the medication can in-terfere with sleep if dosed too close to bedtime. Box 2 details steroid-relatedside effects. Some side effects can be beneficial, such as improved appetite ina cachectic patient, increased energy for generalized fatigue, and inherent anti-emetic activity. Convention dictates that high doses used in the acute period (8to 30 mg/d) should be tapered to the lowest effective dose as soon as clinicallypossible to minimize the negative side effects. The rate of taper should be slow-est once lower doses (4 to 6 mg/d) are achieved to avoid adrenal insufficiencyand rebound edema that can occur especially in patients who have large edemaor longstanding steroid use. An exception is the patient who is about to startradiation therapy who needs sustained moderate doses at least 2 days beforeand during treatment when peritumoral edema can be exacerbated by radiationeffects.

The importance of using steroids in managing brain metastases often meansaccepting the addition of other treatments used to treat the side effects of ste-roids. The increased risk for Pneumocystis carinii pneumonia is greatest when a pa-tient is being treated for 6 weeks or longer and during the tapering period.Prophylaxis is achieved with standard regimens using sulfamethoxazole/trimethoprim or dapsone. Gastrointestinal prophylaxis is warranted for symp-tomatic dyspepsia or reflux. Psychosis or mood lability is best managed withdose reduction, but sometimes short-term neuroleptics are required. Steroidmyopathy, which can develop in a matter of weeks in some patients, is revers-ible only with dose reductions or discontinuation. Premorbid hypertension anddiabetes must also be carefully monitored and standing medications appropri-ately adjusted.

In the absence of clinical seizures, prophylactic use of AEDs is not justified.Prophylactic use of AEDs in brain tumor patients does not significantly de-crease the rate of first clinical seizure and is associated with higher rates of com-plications because of drug interactions [43]. Neurosurgeons occasionally useAEDs in the perioperative period, but these agents can be tapered off postop-eratively if there has been no history of a clinical event. Clinical events in theimmediate postoperative period may not require long-term treatment if theevent can be attributed to temporarily lowered seizure threshold secondaryto irritative craniotomy.

About 20% of patients who have brain metastases present with seizures. TheAED most commonly started in this population tends to be the enzyme-induc-ing agent phenytoin. Enzyme-inducing AEDs can lead to adverse interactionswith other drugs the patient may be taking, including chemotherapy and ste-roids. Newer AEDs, such as levetiracetam and topiramate, which are not

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Box 2: Side effects of long-term steroid use

Common

Hypertension

Cushingoid appearance

Impaired wound healing

Acne

Adrenal insufficiency

Hyperglycemia

Sodium retention

Hypokalemia

Immunosuppression

Myopathy

Osteoporosis

Osteonecrosis

Alterations in mood

Cataracts

Uncommon

Metabolic alkalosis

Peptic ulcer disease

Typhlitis

Benign intracranial hypertension

Spontaneous fractures

Psychosis

Hirsutism

Hiccups

Rare

Allergy

Congestive heart failure

Folliculitis

Impotence

Amenorrhea

Hepatomegaly

Pancreatitis

Seizures

Epidural lipomatosis

Exophthalmos


metabolized by hepatic cytochrome P450 systems, are being used more often inthe brain tumor population. These agents do not have a parenteral formula-tion, however, and therefore cannot be used in the acute setting.

A critical aspect of care for patients who have brain metastases is ensuringaccess to supportive services for neurologic disability. Paresis, gait impairment,incontinence, dysphagia, and cognitive impairment are common manifestationsof CNS disease that require special considerations. Unlike an enlarged or newlung or visceral lesion, progression of disease in the brain or spinal cord cantrigger the need for chronic urinary catheterization, physical therapy, 24-hour supervision, or durable medical equipment for the home. Without recog-nition of these needs, patients can leave clinic encounters with a treatment planfor new CNS metastases but without any mechanisms for dealing with thechange in their level of function.

DEFINITIVE TREATMENTS FOR CENTRAL NERVOUS SYSTEMMETASTASES FROM BREAST CANCERTreatment and prognosis of CNS metastases from breast cancer depend on lo-cation and burden of disease in the CNS and patient characteristics. Definitivetherapies available include radiation therapy, surgery, and chemotherapy. Op-timal treatment is determined by performance status, extent of systemic dis-ease, and distribution of tumor in the CNS. In 1997, the Radiation TherapyOncology Group (RTOG) proposed classifying patients who have brain metas-tases according to prognostic factors identified by a recursive portioning anal-ysis (RPA) of 1200 patients treated with radiotherapy in several RTOG trials(Fig. 2) [44]. This schema has been validated in subsequent studies and manypublications stratify patients by RPA class.

Whole-brain Radiation TherapyThe mainstay of treatment of brain metastases has been WBRT conventionallygiven in 10 fractions to a total dose of 30 Gy. This method remains the first-linetreatment of choice for treating multifocal, symptomatic brain metastases. Pa-tients who are RPA class III, or class II with poorly controlled systemic disease,are best treated with upfront WBRT. Bulky, radiographically evident leptome-ningeal disease of the brain is likewise best addressed with WBRT that can en-compass all sites of disease that may be causing cranial nerve dysfunction orhydrocephalus and increased intracranial pressure. The treatment is effectivein palliating symptoms for most patients and can be completed in 2 weeks,thus minimizing delay in systemic therapy that is often being changed in thesetting of progression. WBRT alone in the breast cancer population is associ-ated with an overall median survival of about 7 to 8 months [45,46]. Survivaldepends on RPA class (23.0 versus 2.3 months for class I and III, respectively)and number of metastases (14.5 versus 4.2 months for single versus multiplemetastases) [46]. Short-term toxicities of WBRT include confusion, fatigue,nausea, scalp erythema, and alopecia. Long-term survivors face an increasedrisk for dementia, and radionecrosis after 1 year, especially if treated with

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higher doses of radiation [47]. Despite treatment, approximately one half of pa-tients succumb to CNS progression. Adjuncts to radiation therapy are being in-vestigated to augment the effects of treatment. Currently, a large phase III trialis being conducted to assess the added benefit of the radiosensitizer efaproxiralin treating brain metastases from breast cancer [48]. The synthetic agent en-ables oxygen release into hypoxic tissue that is more resistant to radiation ther-apy. Although WBRT remains a useful treatment, subpopulations of patientshave been identified that benefit from more focused therapy with surgery orstereotactic radio surgery (SRS).

SurgeryA minority of patients presenting with single or oligo-metastases in surgicallyaccessible locations are well enough to tolerate a craniotomy. Single brain le-sions raise the possibility of alternate diagnoses in patients who have a historyof more than one malignancy, are survivors of active systemic disease for manyyears, or have lesions that are not radiographically classic for metastases. Inthese instances, surgical resection provides a tissue diagnosis. Often, surgeryis required to address acute neurologic symptoms attributable to mass effect.This is especially true for large lesions in the posterior fossa, where decompres-sion lowers the risk for obstructive hydrocephalus and acute decompensation.Certain cases mandate surgery clinically, but the concept of wider use of sur-gery for metastases led to a landmark randomized prospective trial by Patchelland colleagues [10] of surgery for single metastases. Forty-eight patients whohad a Karnofsky Performance Status greater than 70 and confirmed metastasesfrom solid tumors with intermediate radiosensitivity were evaluated for the

Fig. 2. RTOG recursive partitioning analysis classification of brain metastases.


added benefit of resection before WBRT. The surgical group had less frequentlocal recurrence, improved overall survival (40 versus 15 weeks, P < .01), andlonger interval of functional independence (38 versus 8 weeks, P < .005). Ageand the presence of widely disseminated disease had a negative impact on over-all survival in both groups, but a decreased rate of death from neurologic causewas significantly associated with surgery. The survival benefit observed for thisselect population was observed in a similar study by Vecht and colleagues [49],but was not corroborated in a third trial by Mintz and colleagues [50]. Patchelland colleagues [51] conducted a second trial stratified by the use of adjuvantWBRT after complete resection of a histologically confirmed single brain me-tastasis. Radiation significantly decreased the rate of local (10% versus 46%, P< .001) and distant (14% versus 37%, P < .01) recurrence, and death from neu-rologic causes (14% versus 44%, P ¼ .003). Overall survival was not differentbetween the two groups. These data support the use of WBRT following resec-tion of single brain metastases. Breast cancer patients who are treated with sur-gery and WBRT for brain metastases have a median survival of 16 months inretrospective studies in which the selection criteria are not as strict as in the pro-spective randomized studies discussed above [52,53]. In a series of patients whohad single brain metastases as first site of relapse from breast cancer, patientstreated with surgery at diagnosis had a median survival of 23 months [54].These patients are probably a select group with a better prognosis.

Stereotactic RadiosurgeryMany patients present with single or oligo-metastases situated deeply in thebrain inaccessible to surgical resection. Technological advances in radiationtherapy have afforded these patients an alternative. SRS is highly focused ra-diotherapy delivered in a single or several fractions to a discrete area of tissueto a total dose of 14 to 20 Gy. Multiple lesions can be treated at one time. Lin-ear accelerator and gamma knife delivery systems are equivalent. This nonin-vasive procedure is performed on an outpatient basis with minimal to norecovery time, making it a preferred modality of treatment by patients andtheir physicians. Because the maximum tolerated dose of radiation is inverselyproportional to the size of the lesion, tumors are eligible for treatment if theyare less than 3 to 4 cm in diameter. Higher delivered doses are also propor-tional to the risk for radionecrosis (20% versus 5% for WBRT). The risk ishighest in patients who receive SRS for recurrent brain tumors after progress-ing through WBRT. Radionecrosis can be difficult to distinguish from true tu-mor recurrence even with the use of PET imaging. Patients either require long-term use of steroids or resection for pathologic verification and symptomcontrol.

Upfront use of SRS for the treatment of brain metastases is often used asa substitute for surgery, even for resectable lesions. There are currently nodata available directly comparing the two methods. Although SRS has the ad-vantage of being offered to patients who have multiple inoperable lesions, SRSin addition to WBRT has been proven to have a survival benefit only in

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patients who have a single metastasis (6.5 months WBRT þ SRS versus 4.9months WBRT alone, P ¼ .0393) [55]. A recent prospective trial of SRS aloneversus WBRT plus SRS did not show a survival benefit (8.0 versus 7.5 months,P ¼ .42), confirming observations from prior large retrospective studies. Simi-lar to the data for surgery, WBRT decreased the rate of local and distant recur-rence when added to focal therapy with SRS. There was no impact onneurologic cause of death or level of function, however, implying thatWBRT can be deferred and used as salvage therapy while lowering the riskfor radionecrosis [56]. The vast majority of patients enrolled in these random-ized studies had lung cancer. In retrospective studies selected for breast cancerpatients, those treated with SRS for brain metastases had a median overall sur-vival of 10 to13 months [57,58].

ChemotherapyChemotherapy has been generally regarded as ineffective for patients whohave no class I evidence to support any one regimen. By the time brain metas-tases have developed, tumors have likely acquired resistance to many drugsused to treat systemic disease. The blood–brain barrier not only providesa physical barrier to most substances by way of endothelial tight junctions, itis also maintained by active efflux of drugs by p-glycoprotein and multidrugresistance proteins. Although contrast-enhancing metastases have an impairedblood–brain barrier, intracranial pressure dynamics make drug delivery tobrain tumor tissue unreliable, and nonenhancing tumor cells are left untreatedby most agents with activity against breast cancer. Chemotherapy is most com-monly used for patients once surgical and radiation options have been ex-hausted. Brain metastases from breast cancer should not be approached withthe same nihilism as other solid tumors, because response to chemotherapyis slightly more robust. Despite the large number of patients treated with agentssuch as anthracyclines, taxanes, and hormonal agents, response to brain metas-tases is not well captured and mostly anecdotal because they are often an ex-clusion criterion for studies. Some of these adjuvant therapy standards forbreast cancer have shown limited activity in treating brain metastases.

Tamoxifen has been demonstrated to achieve significant concentrations inbrain metastases from breast cancer and has anecdotally maintained responsesin several patients [59–61]. Its efficacy in the brain probably accounts for someof the lowered risk for developing brain metastases in ERþ patients who arewidely treated with the drug. Unfortunately, this also means that most patientsat risk for brain metastases from breast cancer are not likely to respond to hor-mone therapy. Although doxorubicin accumulates poorly in brain tumor tis-sue, the lipophilic formulation has been shown to penetrate brain tumortissue but not to comparable levels as found in extracranial sites. Objective ra-diographic response was seen in brain metastases from breast cancer in onestudy; however, concurrent treatment with WBRT masked the marginal ef-fects of chemotherapy [62]. The high rate of isolated CNS progression in pa-tients treated with taxane therapy addresses the inability of this class of drug


to control intracranial disease [24]. Better success has been met with cyclophos-phamide and antimetabolite-based regimens.

In a prospective study of breast cancer patients who had brain metastases, 20patients were treated with cyclophosphamide, methotrexate, fluorouracil, andtwo were treated with cyclophosphamide, adriamycin, fluorouracil. A total of76% of patients had an objective response after two cycles and 59% had a re-sponse that lasted greater than 6 weeks, with an overall median survival of 25weeks. The study group included patients who had been treated with these reg-imens previously, and 7 patients had recurrent brain metastases at study entry[63]. In a trial of up front treatment of newly diagnosed brain metastases, 100patients were treated with various chemotherapy regimens with a range of re-sponse rates as follows: cyclophosphamide, methotrexate, prednisone 27/52(52%), cyclophosphamide, fluorouracil, prednisone, methotrexate, vincristine19/35 (54%), methotrexate, vincristine, prednisone 3/7 (43%), cyclophospha-mide, adriamycin 1/6 (17%). Thirteen of 35 (37%) of the patients in this studyhad CNS progression and then responded to retreatment with chemotherapy.Median survival for complete and partial responders was 39.5 months and 10.5months, respectively, versus only 1.5 months for nonresponders [64]. Singleagent high-dose methotrexate has also been studied retrospectively in 32 pa-tients of whom 29 had breast cancer with brain or leptomeningeal metastases.Objective response was seen in 29% [65].

The potentially responsive nature of breast cancer CNS metastases to drugtherapy has prompted a search for other agents that can penetrate the brain,regardless of their anticipated activity against systemic disease. Temozolomideis used for gliomas because of its ability to enter the CNS. Unfortunately, it hasdemonstrated poor activity against brain metastases from breast cancer, withzero responses in two studies that included a total of 15 patients who had breastcancer [66,67]. A trial of topotecan for brain metastases in 24 WBRT-naı̈vebreast cancer patients yielded objective response in 38% of 16 evaluable pa-tients. Median survival was 6.25 months, which was not a significant improve-ment over WBRT alone [68]. The combination of cisplatin and etoposide wasstudied in 107 patients who had newly diagnosed brain metastases, 56 of whomhad breast cancer. A total of 38% of breast cancer patients achieved either com-plete or partial response, more so than any other histology (non–small cell lungcancer was second with a 30% response rate). Median survival for breast can-cer patients was nearly 8 months, again comparable to WBRT alone histori-cally [69].

The role of chemotherapy in treating patients who have brain metastasesfrom breast cancer needs to be studied separately in the up front and recurrentpopulations. Patients who have recurrent brain disease often have progressivesystemic disease. Without radiation or surgical options, they need systemic reg-imens that have activity against their extracranial disease and can also be deliv-ered in effective doses to tumor tissue in the brain. These patients who haverefractory and advanced disease face different survival probabilities. The newlydiagnosed patients may or may not be symptomatic enough to require urgent

384 NGUYEN & ABREY

treatment with focused interventions with or without WBRT or may not haveextensive systemic disease. For patients who have nondisabling CNS metasta-ses and advanced systemic disease, chemotherapy theoretically provides an op-portunity to treat both compartments with some success, deferring the need forradiation and surgery. This is a subgroup of patients who are ideal candidatesto study novel agents with expected activity against brain metastases, eitheralone or as adjuncts to WBRT. More randomized studies are needed to under-stand the role of chemotherapy in brain metastases.

MANAGEMENT OF BREAST CANCER LEPTOMENINGEALDISEASEAll of the treatment modalities discussed above are used in patients who haveleptomeningeal disease occurring either in isolation or concomitant with paren-chymal brain disease. Steroids can be effective in treating headache and neuro-pathic pain. Acute presentations of leptomeningeal disease require radiationtherapy. Rarely, a patient who has secondary hydrocephalus can respondquickly to WBRT, abrogating the need for a ventriculoperitoneal shunt. Gado-linium-enhancing leptomeningeal disease is usually defined as bulky diseaseand is best treated with radiation whether in the brain or spine. Large fieldscan lead to severe myelosuppression, especially in heavily pretreated patients.Once diagnosed, bulky disease should be treated regardless of whether it is clin-ically evident. Because survival in this population is so dismal, preventing dis-ability and preserving quality of life are paramount. Response to radiation mayalso make treatment with chemotherapy and intrathecal therapy more likely tobe effective against a smaller tumor burden. Intrathecal therapy penetrates onlythe first few millimeters of tumor tissue and is not effective against thick or nod-ular disease. Thick enhancement either in the spine or brain may impair CSFresorption, increasing the risk for leukoencephalopathy from intrathecal ther-apy that cannot be circulated and eliminated properly. A nuclear flow studyshould be performed before treating with intrathecal agents if there is bulky,radiographically evident leptomeningeal disease. An Ommaya reservoir isthe most reliable and comfortable mode of delivery of drug for patients whousually require multiple treatments. Prophylaxis with steroids for chemicalmeningitis is advised when using liposomal cytarabine. Intrathecal methotrex-ate is generally better tolerated and seldom requires even secondary prophy-laxis with steroids. Aggressive approaches beyond palliative radiation shouldbe reserved for patients who have limited systemic disease and good perfor-mance status.

SUMMARYBrain metastases from breast cancer are a common complication of the diseaseand alter the management of patients more than any other site of distant pro-gression. Certain subgroups of patients are at higher risk for developing CNSdisease, warranting targeted research and perhaps screening for occult disease.The data for various therapies range from anecdotal case reports to large


prospective randomized trials. All options must be considered together and of-fered in a directed way based on the case at hand. Single and solitary metasta-ses that are resectable in relatively healthy patients should be removedsurgically followed by WBRT. Multiple symptomatic metastases should betreated with WBRT. Inoperable single or oligo-metastases can be treated suc-cessfully with SRS with WBRT adding protection from recurrence. SRS for re-sectable lesions has not been proven equivalent or superior to surgery ina prospective randomized trial carries the possibility of radionecrosis and in-complete response. It is a lower-risk, more tolerable procedure, however. Che-motherapy plays a limited role primarily in the recurrent population and meritsfurther study. Delaying or decreasing neurologic causes of death and disabilityare important therapeutic goals that should be included in any trial for breastcancer patients who have advanced disease. While better definitive strategiesare investigated, physicians must remember to optimize use of supportive ther-apies to ameliorate symptoms and improve quality of life.

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Brain Metastases: Old Problem, New Strategies