Brain Metastases and Neoplastic Meningitis

Epidemiology

Brain metastases are estimated to be 10 times more common than primary malignant brain tumors in adults, occurring in 6% to 20% of patients with cancer. However, the exact incidence is unknown because the incidence is derived from disparate data sources (e.g., cancer registries, death certificates) and different type of studies (e.g., population, clinical, autopsy based). Nevertheless, the reported incidence of brain metastases is increasing probably because of improvement of neuroimaging, increased surveillance, and improved control of systemic disease, resulting in prolonged survival.

The most common primary tumors responsible for brain metastases include lung cancer (30% to 80%), breast cancer (5% to 30%), melanoma (5% to 21%), renal cell carcinoma (5.5% to 11%), and gastrointestinal tract cancer (e.g., colorectal cancer, 1.4% to 4.8%). Although brain metastases may arise from any primary cancer, some tumors, such as prostate, oropharyngeal, and skin carcinomas, rarely metastasize to the brain.

Cancer may spread to the brain at various points in the course of disease, but the timeline differs among tumor types. Symptomatic brain metastases are at times the presenting symptoms that lead to the diagnosis of lung cancer. In other cases, the median interval between diagnosis of lung cancer and identification of brain metastases ranges from 2 to 9 months, with about 90% of the lung cancer brain metastases diagnosed within 1 year of initial diagnosis of lung cancer. But in breast cancer, 80% of the patients with CNS involvement are diagnosed after systemic spread was diagnosed, occurring at an interval of 1 to 3 years after initial diagnosis.

As previously stated, one of the reasons the incidence of brain metastases is increasing is attributed to success in controlling systemic disease and prolonged survival. A prime example was seen after the introduction of trastuzumab (anti–human epidermal growth factor receptor 2 [HER2]), which does not cross the blood–brain barrier, the incidence of brain metastases in HER2-positive breast cancer patients increased from 1.6% to 10.5%, mostly because of improved survival provided by trastuzumab.

Other factors suggested to contribute to the incidence of brain metastases include advanced disease stage, gender, race, and tumor-related factors. Within a primary tumor type (e.g., lung, breast, and melanoma), factors such as histology, tumor grade, molecular subtype, and mutation status influence the incidence of brain metastases. For example, most lung cancer brain metastases are secondary to small cell lung cancer (SCLC) and adenocarcinoma ; breast cancer types with higher probability to metastasize to the brain include high-grade cancers, HER2-positive (irrespective of systemic treatment), and triple-negative subtypes. Melanoma subtypes associated with increased risk for brain metastases include mucosal melanoma, head and neck or trunk primary cutaneous melanomas, acral lentiginous or nodular melanoma histologies, and melanoma patients with BRAF or NRAS mutations.

Prevention and Early Detection

It is not clear if screening for brain metastases is beneficial in asymptomatic solid tumor patients; however, because of the high incidence of brain metastases in non–small cell lung cancer (NSCLC) and SCLC, current guidelines recommend brain imaging (magnetic resonance imaging [MRI] with contrast is preferred) at an initial diagnosis of SCLC and for patients with NSCLC stage II and more (optional for stage IB). The decision to perform neuroimaging in patients with other cancer type without known brain metastases should be based on clinical suspicion.

Similarly, because of the high incidence of brain metastases early after initial cancer diagnosis, elective brain irradiation (PCI [prophylactic cranial irradiation]) was suggested for patients with lung cancer in an attempt to reduce the incidence of overt brain metastases, prolong survival, and improve quality of life. This approach was proposed to overcome the brain as a sanctuary site because of the poor penetrance of systemic drugs to the brain parenchyma. The concept of PCI was also evaluated for other solid tumors (e.g., breast cancer) but without clear therapeutic benefit.

There is some evidence that targeted therapies can prevent, delay, or treat early CNS metastases. A phase III trial evaluating capecitabine with or without lapatinib in advanced HER2-positive breast cancer showed that patients treated with capecitabine and lapatinib had a lower rate of CNS disease compared with lapatinib alone (4% versus 13%; P = .45). Whether better systemic control by capecitabine and lapatinib resulted in a lower rate of CNS involvement is unclear. Currently, there are a few ongoing trials evaluating systemic therapies (mainly targeted agents) in reducing the incidence of brain metastases.

Pathophysiology

Brain metastases arise primarily from arterial hematogenous spread. Large aggregates of tumor cells that gain access to the venous circulation are filtered out in lung capillaries before entering the systemic arterial circulation, but individual tumor cells may pass through and lodge in the brain. Tumor cells tend to become trapped where blood vessels decrease in caliber at the gray–white matter junction and distalmost vasculature (the border or “watershed” zones). Metastatic cells then adhere to the endothelial cells, penetrate into the brain parenchyma, and proliferate.

It has been suggested the tumor emboli may also break off from lung metastases or primary lung cancers to travel to the brain via the arterial circulation. Cells from pelvic or abdominal cancers may gain access to the posterior fossa or leptomeninges through Batson's vertebral venous plexus without passing through the lungs.

The distribution of metastases is roughly proportional to the relative blood flow to different regions; approximately 80% of brain metastases are located in the cerebral hemispheres, 10% to 15% in the cerebellum, and 1% to 5% in the brainstem. Posterior fossa metastases appear to arise disproportionately from pelvic or abdominal primary tumors.

Most brain metastases are very well circumscribed. Although extensive associated edema may be present, the tumor cells do not tend to infiltrate into surrounding brain tissue, in contrast to primary malignant brain tumors. Most brain metastases are solid, but they may be heterogeneously enhancing or cystic because of necrosis, keratin deposits in squamous cell carcinoma, or mucin secretion from adenocarcinomas. Brain metastases may be hemorrhagic, particularly from melanoma, renal cell carcinoma, choriocarcinoma, and, less frequently, bronchogenic carcinoma.

Clinical Presentation

The possibility of brain metastases should be suspected in any patient with cancer who experiences new neurologic signs or symptoms. Symptoms often worsen gradually over time from a growing tumor and associated edema. Less often, acute neurologic symptoms may occur as a result of hemorrhage. The most common presenting symptoms are fatigue, headache (24% to 53%), focal weakness (16% to 40%), altered mental status (24% to 31%), gait ataxia (9% to 21%), seizures (15% to 18%), and difficulty in speech (12%) depending on the location of the lesion within the brain parenchyma and degree of edema. Other common symptoms include insomnia, mood changes, and difficulty in concentrating, loss of appetite, and nausea. Patients who present with drowsiness or dyspnea tend to have a poor survival and might need urgent intervention (e.g., corticosteroids). Symptoms may worsen after treatment, and potentially reversible processes such as increasing edema from treatment should be suspected and treated accordingly. Severe symptoms and worsening of symptoms can serve as a prognostic tool and assist the physician to set appropriate care goals with the patient and her or his caregiver, plan an appropriate treatment approach, and have time to address end-of-life concerns.

Diagnosis

It is widely accepted that MRI is the best diagnostic to detect brain metastases and evaluate the number, size, and location of metastases. Standard MRI includes T2-weighted and pre- and postgadolinium-enhanced T1-weighted sequences. A postcontrast fluid-attenuated inversion-recovery (FLAIR) sequence is helpful in visualizing small metastases near cerebrospinal fluid (CSF) spaces and evaluate the extent of edema ( Fig. 55.1 ). High-dose gadolinium and 1-mm slices may aid in visualizing small brain metastases and are also useful for SRT treatment planning. The role of MRI in characterizing brain metastases is evolving. Functional imaging techniques, such as magnetic resonance spectroscopy and perfusion and diffusion, may aid in distinguishing metastatic lesions from other enhancing lesions such as a primary brain tumor or nonmalignant processes. New studies suggest the potential use of morphology and texture analysis of MRI in differentiating between histologic subtype within a given group (e.g., lung adenocarcinoma versus squamous cell, subtypes of breast cancer).

In patients who were previously treated for brain metastasis or exposed to RT, the differential diagnosis of an enhancing brain lesion also includes radiation necrosis. The location of the lesion with respect to previous radiation treatment can aid in the diagnosis; however, it is often difficult to differentiate between the two, and additional diagnostic evaluation may be needed. These may include MRI spectroscopy, perfusion imaging, or both. Positron emission tomography (PET) using fluorodeoxyglucose (18F or FDG) has low sensitivity and specificity in the brain but may help in differentiating viable tumor from radiation necrosis. Correlation or coregistration with contrast-enhanced-MRI can increase the diagnostic accuracy of PET-FDG in these cases. Other amino acid–based PETs (e.g., O-(2-[18F]fluoroethyl)-L-tyrosine [FET], L-[methyl-11C]methionine [MET]) were also shown to be beneficial in diagnosing brain lesions and differentiating viable tumor from necrosis. Delayed contrast and perfusion MRI (TRAMs) is a new method that can aid in differentiating necrosis from viable tumor and was shown to correlate with histologic findings of viable tumor or necrosis in patients with primary and metastatic brain lesions.

The differential diagnosis of an enhancing or hemorrhagic intracranial lesion also includes primary brain tumor, CNS lymphoma, abscess, encephalitis, cerebral infarct or hemorrhage, progressive multifocal leukoencephalopathy, multiple sclerosis, and demyelinating disease. However, tissue confirmation (biopsy, resection) may be warranted if there is doubt about the diagnosis or if a solitary brain lesion seen in a patient without a history of cancer (or with other accessible lesions) or a history of cancer but no other known metastatic disease.

Even if the diagnosis seems obvious in patients with a known cancer, tissue confirmation might have significant implications. In Patchell's 1990 publication that established the role of surgery before whole-brain radiotherapy (WBRT) in patients with a known systemic cancer, 11% of 54 patients with a single brain lesion that was thought to be a metastasis turned out to have glioblastoma, low-grade astrocytoma, abscess, or an inflammatory process. Imaging has much improved to aid in diagnosis, but the differential diagnosis of an enhancing brain lesion should be kept in mind.

Prognostic Factors

In general, brain metastases are associated with a poor prognosis. Despite major advances in cancer diagnosis, cancer treatment, and brain imaging, the overall survival time of patients with brain metastases treated with WBRT without surgery or stereotactic radiosurgery (single fraction, SRS) has remained at about 2 to 6 months since the 1950s. Although some patients will survive 1 to 2 years, only approximately 2.5% will survive more than 5 years with aggressive treatments.

Prognostic factors have been evaluated in several large series. Gaspar and colleagues identified three prognostic groups by using a recursive partitioning analysis (RPA) of more than 1100 patients enrolled in three consecutive Radiation Therapy Oncology Group (RTOG) trials. The median survival period was 7.1 months for RPA class 1, consisting of patients younger than 65 years old with a Karnofsky performance status (KPS) of 70 or greater, controlled primary tumor, and no extracranial metastases. Patients with KPS less than 70 (RPA class 3) had a median survival period of only 2.3 months; the median survival period was 4.2 months for the remaining patients (RPA class 2). Yamamoto and colleagues suggested a subclassification of the RPA II into three categories to better identify patients who might benefit from more aggressive approach.

Sperduto and colleagues developed a newer prognostic index for patients with brain metastases termed the Graded Prognostic Assessment (GPA) based on a database of 1960 patients accrued to several RTOG brain metastasis protocols that was validated and refined with diagnosis-specific (DS-GPA) prognostic indices based on an independent, multi-institutional retrospective analysis of 4259 other patients with brain metastases treated with WBRT, SRS, or both ( Tables 55.1 and 55.2 ). Sperduto and colleagues demonstrated a wide range of survival (from 3.4 months to 25.3 months) for breast cancer patients with brain metastases. The prognostic analysis for breast cancer patients was revised to include primary tumor subtype that was significant for survival.

Treatment

Radiation Therapy

Whole-Brain Radiotherapy

Radiation therapy for the treatment of brain metastases has changed dramatically over the past several decades. In the past, the standard treatment for brain metastases was WBRT covering the entire intracranial contents ( Fig. 55.2A ). The benefits of WBRT were first described in the 1950s and 1960s. In these early studies, significant symptomatic improvement was noted in about 60% of patients, and the median survival time ranged from 3 to 6 months compared with an expected median survival time of 1 to 2 months without treatment. Moreover, WBRT was widely available, easily started without complicated planning, treats both gross and subclinical disease, and provides palliation for symptoms. All these made WBRT the standard of care for brain metastases for many years.