Brain metastasis in patients with cancer can be indicative of multisystem spread or lead to neurological demise if not locally controlled, and is associated with poor survival and high morbidity. Compared with metastasis to other areas of the body, brain metastasis possesses a unique biology that confers high resistance to systemic therapies. This phenomenon has been historically attributed to the inability of chemotherapeutic agents to pass through the blood-brain barrier. Recent studies challenge this premise, revealing other potentially targetable mechanism(s). Therapies that exploit recent advances in the understanding of brain metastasis are still in early stages of development. Encouragingly, and discovered by happenstance, some molecularly targeted drugs already appear to have efficacy against certain tumors and accompanying cerebral edema. In the meantime, conventional treatment modalities such as surgery and radiation have iteratively reached new levels of refinement. However, these achievements are somewhat muted by the emergence of magnetic resonance (MR)-guided laser interstitial thermal therapy, a minimally invasive neuroablative technique. On the horizon, MR-guided focused ultrasound surgery is similarly intriguing. Even in the absence of further advances, local control is frequently achieved with state-of-the-art therapies. Dramatic improvements will likely require sophisticated approaches that account for the particular effects of the microenvironment of the central nervous system on metastasis.
Current Therapeutic Strategies
Surgery remains a highly successful treatment approach for accessible brain tumors (Figure 2). Its judicious application necessitates an understanding of the limitations and efficacy of various surgical strategies and technologies. The most significant technical advances in surgery over the last decade have arguably occurred in the field of preoperative brain mapping. These advances include functional MRIs with fiber tract mapping and transcranial magnetic stimulation coupled with three-dimensional MRI renderings. More importantly, the advances in systemic therapy and radiation therapy have had the greatest influence on surgical indications. Better systemic therapies have increased the pool of patients eligible for surgery, while enhanced screening and improved radiosurgery techniques are often used to manage smaller lesions, obviating the need for a craniotomy.
Surgery for a single lesion originating from a solid cancer in an accessible location, and in a patient who has very limited or no systemic cancer and an absence of leptomeningeal infiltration, classically results in significant improvements in neurologic function and improved survival.[25,26] Indications are less defined in patients with moderate systemic tumor burden or multiple brain metastases.[27,28] For these patients, especially if radiation has already been attempted, a craniotomy may be the only remedy that can provide rapid relief of symptoms linked to mass effect, such as intracranial hypertension, seizures, obstructive hydrocephalus, or peritumoral edema. Deviation from classical indications for surgery is often considered when the patient has significant extracranial disease but is eligible for other lines of effective systemic therapies. In addition, the role of surgery for multiple metastases is currently being redefined. Because multiple lesions often require separate craniotomies, there is a higher cumulative probability of complications developing as a result of the multiple surgeries. Nevertheless, this risk seems justified, as median patient survival time is 9 to 14 months, which is 3 to 6 months longer than the survival of those who are treated solely with radiation.[30-32] In fact, surgical removal of all lesions in patients with up to three brain metastases can lead to survival comparable to that of patients with a single metastasis.
Surgical technique has been shown to influence local recurrence rates. Tumors resected in a piecemeal fashion, which violates the tumor capsule, have a recurrence rate 1.7 times higher than that of tumors removed with circumferential resection (en bloc). En bloc resection has been shown to be particularly important for lesions of the posterior fossa and those in contact with cerebrospinal fluid pathways. Moreover, piecemeal resections are not always safe because of the size of the lesion or the proximity of eloquent cortex. To reduce the incidence of local recurrence, Yoo et al suggested a microscopic total resection approach in which a 5-mm margin of normal-appearing tissue is removed by ultrasonic aspiration. Compared with standard piecemeal gross total resection without adjuvant therapy, microscopic total resection reduced 1-year local recurrence rates from 59% to 29%. Since most resection cavities are now treated with postoperative stereotactic radiosurgery (SRS), this finding may be most relevant to the resection of metastatic tumors progressing despite radiation or initial surgery for lesions known to have high radioresistance.
Whole-brain radiotherapy (WBRT) is often utilized for multiple and disseminated metastases and for salvaging stereotactic radiation therapy failures. Studies have shown that 64% to 83% of patients with multiple metastases who undergo WBRT experience significant symptomatic improvement and a mean increase in survival of 2 to 6 months. Combined with surgery, WBRT drastically lowers recurrence rates to 10% to 18%, compared with 46% to 70% with surgery alone. However, the toxicity of WBRT should be considered. Although WBRT was initially found to be minimally toxic, recent studies have shown potential adverse short- and long-term effects, especially in the elderly population.[38,39]
SRS focuses beams of radiation on the tumor(s). The convergence enhances tumoricidal effect and results in a rapid dose drop-off in normal tissues, allowing for treatment of lesions adjacent to critical structures. The efficacy of SRS for brain lesions is generally encouraging, with local control rates ranging from approximately 64% to 94%.[41-49] Lesions less likely to respond are generally larger than 2 cm3, receive less than 18 Gy of radiation, or have a radiation-resistant histology (eg, melanoma or renal cell carcinoma).
There are overlapping considerations when deciding whether to use SRS alone, as an adjunct to surgery or WBRT, or not at all. One widely used determinant has been lesion number. For single brain metastasis, SRS alone is potentially as effective as surgery with SRS of the resection cavity when the lesion is small and radiosensitive.[50-52] SRS alone is usually a better option than surgery if the lesion is surgically inaccessible, or if the patient has uncontrolled systemic metastasis or is a poor operative candidate due to other medical conditions. In practice, surgery is often performed to resect or cytoreduce a bulky metastatic lesion, allowing SRS to be used adjunctively. With combined treatment, 1-year local control rates have ranged from 80% to 93%, with salvage WBRT (typically for distant metastasis) required in 33% to 46% of patients.[53-55] The substantial rate of salvage WBRT then raises the issue of whether the traditional approach of surgery with postoperative WBRT is a more rational option. A recent retrospective study by Patel et al provides some insight. The investigators found that in a series of 132 patients, overall survival and local control were similar between patients treated with surgery plus SRS and those treated with surgery plus WBRT. WBRT was associated with a higher rate of distant brain control (70% vs 48% at 1 year; P = .03) and greater freedom from leptomeningeal disease (87% vs 69% at 18 months; P = .045) compared with SRS; however, radiographic leukoencephalopathy was remarkably higher with WBRT (47% vs 7% at 12 months; P = .001). Therefore, if these results hold true in further studies, the choice of surgery followed by SRS or WBRT will be determined by balancing certain tradeoffs in the light of each patient’s circumstances.
SRS is also commonly used to treat multiple (ie, two to four) brain metastases. In a number of studies, SRS was associated with significantly improved local control compared with WBRT, although overall survival was equivalent.[57,58] When used in conjunction, SRS plus WBRT increases distant brain control without affecting survival.[59,60] However, treatment times are longer and there is a higher probability of neurocognitive side effects.[56,61,62] Thus, the limited benefit of this approach is unlikely to justify the additional effort and morbidity.
There has been a reluctance to use SRS for more than four brain metastases because of restricted inclusion criteria for several randomized studies. Experience with aggressive SRS treatment has blurred the distinction between oligo and disseminated metastases, the latter once solely within the purview of WBRT. Multiple large retrospective studies have demonstrated that patients with up to 15 lesions treated with SRS had a similar clinical course to those with 1 to 4.[63-66] It has been suggested that total tumor volume is more important than the absolute number of lesions; however, the point at which this notion ceases to be true requires further investigation.
Chemotherapy and targeted agents
With few exceptions, most notably germ cell tumors and small-cell lung cancer, metastatic brain tumors do not respond to systemic chemotherapy.[26,68] However, molecularly targeted therapies have shown some promise against brain metastases, especially those that are “oncogene addicted.” One such example is seen in non–small-cell lung cancer (NSCLC) that possesses activating epidermal growth factor receptor (EGFR) mutations. Complete and partial response rates to tyrosine kinase inhibitors have been recorded in clinical studies: Rates of response with gefitinib ranged from 10% to 38%, with a median duration of 9 to 13.5 months, and similar findings were documented with erlotinib.[70,71] These treatments also improved overall survival rates.
Also, a remarkable number of patients with human epidermal growth factor receptor 2 (HER2)-positive breast carcinoma have had a favorable response to lapatinib, a tyrosine kinase inhibitor that targets the C-terminus domain of HER2 and EGFR receptors. In a multicenter phase II trial, which included 242 patients who had received prior trastuzumab and cranial radiation treatment, 6% of patients had an objective response and 21% had at least a 20% volumetric reduction with lapatinib alone. In a subgroup of 50 patients who entered an extension of this study, 20% experienced an objective response and 40% experienced at least a 20% volumetric reduction in their brain metastasis with lapatinib plus capecitabine. Although the current efficacy of targeted therapy is modest, these results inspire great hopes for future systemic treatments.
Use of bevacizumab for treatment of malignant brain edema associated with brain metastasis
A treatment also worth noting is a targeted antiangiogenic approach to managing severe cerebral edema following SRS.. In a small clinical trial, eight patients were treated with CyberKnife and bevacizumab (Figure 3). The rationale was to use bevacizumab to block VEGF in leakage-prone capillaries to decrease the amount of cerebral edema. Seven of the eight patients had drastically improved neurologic functioning, while only one patient suffered bevacizumab-related hypertension. This novel approach warrants further investigation and should be considered for this frequently encountered clinical scenario.
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