Description
Initial assessment. Initial assessment of the patient by a multidisciplinary team is critical to choosing the optimal management strategy for patients with brain metastases. The evaluation of a patient with suspected brain metastases includes a complete history, physical and neurologic examination, Karnofsky Performance Status determination, and a review of the patient's primary tumor history, if applicable. Imaging should ideally include a gadolinium-enhanced MRI scan of the brain.
If a metastatic lesion is suspected based on the clinical evaluation and brain imaging, and if the primary site is unknown, a workup to identify the primary tumor is typically appropriate. The lung is the primary site in 70% of cases in which brain metastases are the initial presentation of an extracranial primary tumor; therefore, a chest CT scan is the most productive diagnostic test, although PET/CT may also help define the extent of disease (54). Inclusion of a CT scan of the abdomen may reveal the occasional renal or gastrointestinal primary tumor; further radiologic studies are rarely diagnostic.
The management of brain metastases requires multidisciplinary input from neurosurgery, neuro-oncology (where available), medical oncology, and radiation oncology. The choice of use and sequencing of systemic therapy or local therapy to manage brain metastases depends on size, location, and histology (including molecular characteristics of the tumor) in addition to patient-specific factors, such as age, Karnofsky Performance Status, and extracranial disease status. Local therapies of surgery and radiation therapy remain the standard of care. However, for select patients with small, asymptomatic metastases, upfront CNS-active systemic therapies can be considered.
Surgical resection. Surgical resection for brain metastasis can be diagnostic and therapeutic. For surgical resection, the goal is to allow for maximal resection of the tumor while preserving as much normal tissue as possible. The operating room team must be proficient in surgical approaches to brain lesions, image-guided neuronavigation, intraoperative neuromonitoring, and neuroanesthesia for cerebroprotection. Techniques and equipment important for surgical resection include volumetric CT and MRI image-guided neuronavigation, intraoperative ultrasound, and occasionally intraoperative electrophysiological monitoring and mapping (evoked potentials and direct brain stimulation) when tumors involve or are adjacent to eloquent brain (37). Intraoperative ultrasound can facilitate maximal resection (31). The refinement of imaging modalities that highlight white matter tracts, when combined with more recently developed tubular retractor systems, has allowed for access to deeper-seeded lesions with promising results (15).
In the setting of surgical resection, there may be a transient worsening of neurologic function due to irritation associated with dissection. This is typically an exacerbation of preexisting symptoms related to the mass effect of the tumor itself or associated edema. A short course of corticosteroids (1 week or less in most cases of surgical resection) may be helpful. Permanent neurologic deficit is unlikely to result despite a transient worsening for up to a week that parallels the time course of postoperative cerebral edema.
Postoperative radiation therapy. Postoperative radiation therapy for brain metastases is needed to reduce local recurrence. Even after gross total resection of brain metastasis, there is a high likelihood of local recurrence in the operative bed, ranging from 50% to 70% (39; 32). Randomized data have shown that adding postoperative radiation therapy after resection reduces the risk of local recurrence in the resection site. Although this was originally done with whole-brain radiation therapy, focal postoperative radiosurgery to the resection bed was found to have a lower incidence of neurocognitive toxicity without compromising overall survival (04). However, the use of single-fraction stereotactic radiosurgery after surgery is associated with an increased risk of local recurrence, including leptomeningeal disease, and higher rates of radionecrosis. Many centers treat the postoperative bed with a hypofractionated approach of 5 to 10 fractions to allow for more generous postoperative margins, which achieves lower late toxicity and more durable overall disease control (07; 17).
One concern about postoperative radiation therapy has been the presence of postsurgical nodular leptomeningeal recurrence (also termed pachymeningeal recurrence), which is the appearance of diffuse cerebrospinal fluid-based metastases seen along the meningeal surfaces after craniotomy for tumor resection. In some series, this occurs in up to 10% to 20% of patients within 1 year (08; 36). To reduce this risk, either fractionated radiation therapy that covers the entire tumor bed and surgical tract is very effective (07), or preoperative stereotactic radiosurgery can be employed to prevent tumor seeding at the time of resection. Preliminary data have shown good rates of local control with reduced incidence of dural-based recurrences (41). Whether preoperative stereotactic radiosurgery is equivalent to postoperative radiation therapy is being compared in ongoing randomized trials.
Stereotactic radiosurgery. Stereotactic radiosurgery for intact brain metastases is a noninvasive alternative to surgery. In patients with intact, small (less than 2 cm) brain metastases receiving stereotactic radiosurgery, the goals of treatment are to deliver an ablative dose of radiation to control the tumor while limiting the risk of injury to nearby brain structures. There are several different delivery systems for stereotactic radiosurgery, as described above, which differ in technical aspects, but all provide similar treatments with similar outcomes (13).
The process of stereotactic radiosurgery begins with immobilization and simulation. Immobilization is key to the reproducibility of treatment delivery. Some systems may use neurosurgical pin frames, whereas others use a dental mold immobilization system to provide an accurate setup. “Frameless” approaches using thermoplastic masks have become more common to maximize patient comfort.
Once the immobilization is made, a CT scan is performed, typically with intravenous contrast to provide anatomic data on the tumor location. This can be fused in silico with prior MRI scans, and the tumor is outlined. Critical normal structures, including the optic pathways, cochlea, and brainstem, are also identified as areas that should be spared during stereotactic radiosurgery planning.
The goal of radiation planning is to deliver the prescribed dose of radiation to the tumor while limiting the dose to normal brain and other key critical structures. Typically, the dose prescribed for smaller metastases is 18 to 24 Gy, whereas larger lesions may require lower doses to maintain safety as defined in an initial dose escalation study (45). To facilitate a rapid dose fall-off to normal tissue, the center of the target often receives doses 10% to 50% higher than the nominal prescription dose. The dose to normal brain tissue, as measured by the volume of brain receiving 10 to 12 Gy, is also monitored as a parameter to limit radionecrosis (35).
For larger lesions or those near critical structures, approaches using fractionated stereotactic radiosurgery have been shown to safely provide good local control. This technique uses the precision setup for stereotactic radiosurgery but delivers the dose over multiple treatments. This increased fractionation of dose allows for DNA repair to occur in normal tissues and, thus, reduces the risk of late radiation injury and radionecrosis. These approaches can range from as few as two fractions to upwards of 10, depending on the total dose and the dose delivered per fraction. Ultimately, these decisions are made by the treating radiation oncologist, taking into account disease histology, tumor location, volume of target, presence of edema, and hemorrhage, as well as patient factors, such as the need to continue systemic therapy and the ability of the patient to come for multiple days of treatment.
One of the advantages of stereotactic radiosurgery is that it minimizes the recovery time or interruption of systemic therapy. However, it is clear that there may be interactions with conventional chemotherapy, targeted therapy, and immunotherapies. Although the literature is limited, targeted therapies are usually held at least for the days surrounding stereotactic radiosurgery at a length dependent on the half-life of the drug as well as the need for ongoing systemic control. For chemotherapies, stereotactic radiosurgery is typically delivered during an off week of the drug infusion to try to limit the potential toxicity of concurrent delivery. With antibody-based drugs, such as immune checkpoint blockade (34; 42) and antibody-drug conjugates (29), there may be increased risks of adverse radiation toxicity with some agents, but the kinetics of drug response are less clear, and more data are required to determine if alterations in dose or schedule of stereotactic radiosurgery are needed to limit toxicity.
Follow up. After local therapy, patients are routinely followed with serial MRI every 2 to 3 months. For focal approaches with stereotactic radiosurgery or surgery, there remains at least a 50% risk of additional metastases appearing in the untreated brain. MRI surveillance is also helpful in identifying radionecrosis, which can occur as soon as 4 to 6 months after stereotactic radiosurgery and as late as several years after treatment.
Indications
For appropriate decision-making, it is essential to have a best estimate of the patient's survival, factoring in the primary disease, the extent of noncentral nervous system disease, and pertinent comorbidities. If age or general medical status indicates a risk for general anesthesia, evaluation by a neuroanesthesiologist is helpful to clarify that risk. In some cases, surgical resection can be accomplished under local anesthesia with intravenous sedation, reducing the medical risk of the surgery.
A second important factor in treatment consideration is the number and volume of metastatic lesions, which help to decide whether a focal therapy like surgery or stereotactic radiosurgery should be considered. Multiple randomized trials have shown that for patients with 1 to 4 brain metastases, treatment with stereotactic radiosurgery can provide local control of metastases with less impact on quality of life and neurocognitive function compared to whole-brain radiation therapy without compromising overall survival (01; 09; 26; 02).
However, although these studies demonstrated that omitting WBRT was not associated with worse survival, there is an increased risk of failure in the remaining brain. An individual patient data meta-analysis of three randomized trials comparing stereotactic radiosurgery with or without WBRT showed that patients receiving only focal therapy had a 53% risk of new brain metastases compared to 34% of those receiving WBRT (43).
Although the original studies were limited to four or fewer metastases, newer prospective studies have demonstrated the safety of treating patients with more than 10 metastases with stereotactic radiosurgery alone (50). Multiple randomized trials are determining whether treating patients with a larger number of brain metastases with stereotactic radiosurgery alone is not associated with inferior survival to WBRT.
For patients with a limited number of metastases and a reasonable prognosis of greater than 3 to 6 months, decisions regarding surgery or stereotactic radiosurgery rely on the integration of several factors. Generally, surgery is favored for lesions larger than 2 to 3 cm or symptomatic lesions with significant mass effect or edema. Another indication for surgery is to establish a histologic diagnosis in patients for whom there is no prior diagnosis of metastatic cancer. In some patients, especially for metastatic melanoma or non-small cell lung cancer where immune checkpoint inhibitors are considered, resection is favored to more rapidly taper a patient off of immune-suppressing steroids. One potential benefit of a surgical approach that has gained favor is the ability to perform molecular testing of brain metastases, as it has become clear that unique mutations may be present in the CNS, potentially offering targeted therapy options that may not have been apparent in the primary tumor site (46). Combined treatments, including surgical resection of one or more of the multiple lesions followed by radiosurgery for the remaining lesions, are also a reasonable treatment strategy in many patients.
Stereotactic radiosurgery is often considered for patients who do not meet those criteria, as well as in patients who are medically unfit for craniotomy or anesthesia. Additionally, some lesions located in deeper, eloquent regions are unresectable without significant deficit and, thus, are treated with local radiotherapy. Stereotactic radiosurgery also may be preferred in patients with significant extracranial disease burden, as there is little to no recovery time and patients can transition directly to systemic therapy.
For the small subset of lesions with no clear advantage for surgery or stereotactic radiosurgery, the likelihood of local control of the lesion is similar regardless of the approach taken (11). The choice is often based on patient preference or other logistical factors.
Contraindications
The major contraindications to surgery are a life expectancy of less than 4 to 6 months and a Karnofsky Performance Status score of less than 70 (without expectation of significant improvement after surgery). For surgical resection, the patient's medical condition (ie, risk of undergoing general anesthesia) must be considered. However, increasing the use of minimally invasive stereotactic and image-guided techniques has allowed for shorter anesthesia times and lower complication rates, thereby making surgical resection a viable option even for patients with significant comorbidities. In patients for whom surgical resection is not feasible, placement of a ventricular peritoneal shunt to reduce the risks of obstructive hydrocephalus may facilitate radiation therapy in cases with significant mass effect.
The size and location of the metastatic tumors usually dictate whether surgical resection or stereotactic radiosurgery is the more appropriate treatment strategy. Lesions larger than 3 cm in diameter are rarely candidates for single-fraction stereotactic radiosurgery but can often be effectively controlled with hypofractionated stereotactic radiosurgery. In short, both surgical resection and radiotherapy are essential in the management of brain metastases, and any care team managing this patient population must be able to offer both treatment strategies.
Outcomes
The goal of surgery for brain metastases should be the preservation or improvement of functional neurologic status, particularly when long-term control of systemic disease is feasible. The primary goal of both surgery and stereotactic radiosurgery is to achieve local control of the lesion or lesions treated. In large multi-institutional series, the likelihood of local control after stereotactic radiosurgery ranged from 80% to 95% at 1 year, depending on numerous factors, including tumor cell histology and extent of resection. The likelihood of local control for tumors with surgery and preoperative or postoperative radiation is similar, suggesting these approaches are equivalent.
The compilation of multi-institutional data has resulted in a disease-specific graded prognosis assessment (ds-GPA) that estimates survival for patients with brain metastases (47). This metric is based on Karnofsky Performance Status, presence of extracranial disease, age, and other factors related to disease type. For lung cancer, the incorporation of molecular drivers and PD-L1 status has resulted in the Lung-GPA (48). Thus, an estimation of outcomes is highly dependent on the primary tumor and the likelihood of disease control with systemic therapy. For the best prognosis, the median survival of patients with lung cancer brain metastasis is greater than 4 years.
Quality of life measures are meaningfully lower among patients with symptomatic brain metastases compared to cohorts of cancer patients without brain metastases (53). Craniotomy for brain tumors generally may affect quality of life measured in the immediate postoperative period; however, an improvement in quality of life is seen in most patients by 30 days postoperatively (27). Similarly, stereotactic radiosurgery does not appear to adversely affect quality of life measurements for many patients (06).
Adverse effects
Complications of surgery for brain metastases include death (operative mortality defined as death due to any cause within 30 days of surgery), neurologic worsening, and other complications, such as infection, pulmonary embolism, and myocardial infarction. The operative mortality with surgical resection in a series of 3500 patients from the National Surgical Quality Improvement Project database was 4%. The most common complications were venous thromboembolism, pneumonia, urinary tract infection, and sepsis. Cardiac events tended to occur in 0 to 2 days, whereas other events were more likely at 4 to 6 days. Infratentorial lesions were more likely to be associated with complications (21).
For stereotactic radiosurgery, there is little acute toxicity, with transient fatigue and transient patchy hair thinning being the most common. Minor headaches may occur. There is a risk of seizure after stereotactic radiosurgery of 5% to 10% (30), although the use of long-term prophylactic anti-seizure medications is not recommended (52). Some centers will use a short course of levetiracetam or lorazepam immediately after stereotactic radiosurgery to reduce the seizure risk in the immediate post-stereotactic radiosurgery setting.
Treatment-related necrosis is a late-occurring event typically found by increased enhancement and edema around the site of prior stereotactic radiosurgery. It can occur anywhere from a few months to years after stereotactic radiosurgery. This can be difficult to distinguish from tumor progression. Despite multiple studies of brain PET, MR spectroscopy, and other advanced imaging techniques, no reliable radiographic test can distinguish between treatment-related necrosis and tumor progression. More recently, perfusion MRI has been studied in this context, with increased perfusion more likely to represent active disease and hypoperfusion more likely to represent necrosis (14). However, our most reliable indicators of necrosis remain pathologic confirmation at surgery or clinical behavior.
Patients are typically followed with serial MRIs and treated with steroids if they have neurologic symptoms. Surgical resection can be used to establish a diagnosis of necrosis or tumor progression to help guide therapy and relieve symptoms. Laser interstitial thermal therapy can be used to debulk the area of necrosis and improve symptoms. In patients with refractory symptoms or steroid intolerance, bevacizumab is sometimes considered and has shown promising results (51).
Special considerations
Pregnancy. Fortunately, brain metastases are relatively uncommon in females of childbearing age. If a pregnant woman should be diagnosed with brain metastasis and surgery (open excision or stereotactic radiosurgery) is indicated, the risk to the fetus of either a general anesthetic (for open excision) or radiation exposure (for stereotactic radiosurgery) must be considered. Open excision under local anesthesia may be an alternative that presents less risk to the fetus. Unless the metastasis is diagnosed late in the pregnancy (or is small and asymptomatic), it is unlikely that surgery could be postponed until after delivery. If possible, an alternative option may be to delay the surgery until a more favorable time for the fetus (eg, in the second trimester).
Elderly patients. Given that solid tumors are more common with increasing age, the management of brain metastases in an elderly population is an important topic. SEER analysis suggests that patients more than 65 years of age with brain metastases have a worse prognosis than younger cohorts (28). However, outcomes after craniotomy for brain metastases for patients older than 65 appear to be similar to those in younger patients (23). Frailty measures, which incorporate age and other factors, are generally associated with poorer outcomes for craniotomy (21). For fit patients, a craniotomy may be an option even for octagenarians (16). However, for many of these patients, a noninvasive radiation approach may be favored.
Clinical vignette
Case 1. MC was a 69-year-old woman who presented with confusion and word-finding difficulties. Brain MRI was obtained and showed a dominant 2.5 cm enhancing lesion in the left temporo-occipital lobe. Multiple other enhancing lesions were seen, including a 7 mm left frontal gyrus. Chest CT showed no evidence of a primary tumor. After multidisciplinary discussion, resection of the left temporal lesion was recommended. She was taken for a left temporal craniotomy, and the tumor was able to be removed en bloc. Pathology from the surgery showed metastatic adenocarcinoma, and immunohistochemistry was consistent with a lung primary origin. Postoperative MRI showed no evidence of residual disease. She was evaluated by thoracic medical oncology, neuro-oncology, and radiation oncology. Postoperative radiation therapy was recommended for the resection cavity, along with stereotactic radiosurgery to the residual lesions. The resection cavity was treated with 3D conformal radiation to 30 Gy in 10 fractions, and stereotactic radiosurgery was delivered to the intact lesion, 18 Gy in 1 fraction. Following the completion of radiation therapy, she was treated with carboplatin, pemetrexed, and pembrolizumab. She had no evidence of further CNS disease over 1 year after presentation.
