Mr. Johnson of Stanford University School of Medicine has no relevant financial relationships to disclose.)
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from AbbVie as a guest speaker, from NewLink Genetics and Reneuron for consulting work, and from Monetris as an advisory board member.)
Although brain metastases are thought to be at least 5 times as common as primary brain tumors—affecting about 200,000 people each year in the United States—suboptimal treatment impairs quality of life and survival. An experienced team involved in the diagnosis and treatment (surgical and/or radiosurgical where indicated) will enhance functional survival.
• Metastatic brain tumors are thought to be at least 5 times as common as primary brain tumors and occur in upwards of 40% of patients with metastatic cancer depending on the histology and stage of cancer.
• Many brain metastases can be cured or controlled with a combination of surgical resection, stereotactic radiosurgery, and/or whole brain radiation therapy.
• Lung, breast, and melanoma are the 3 most common primary tumors that metastasize to the brain.
• The optimum management of a patient with brain metastasis or metastases benefits from a multidisciplinary team consisting of neurosurgery, radiation oncology, medical oncology, neuroradiology, neuropathology, and the patient s primary physician.
Historical note and terminology
Tumors that have metastasized to the brain have been identified on autopsies for centuries. Grant's report of Harvey Cushing's series in 1926 was the first regarding patients who underwent surgical excision of brain metastases (Grant 1926). Early reports of operative mortality rates for metastatic brain tumor resection ranged from 20% to 38% (Cushing 1932; Stortebecker 1954; Simionescu 1960). For those patients who survived the immediate postoperative period, median survival was approximately 6 months (Cairncross and Posner 1983). During the mid-twentieth century, whole brain radiotherapy (WBRT) was shown to increase survival significantly, and thus, WBRT soon became the primary treatment modality for patients with brain metastases (Chao et al 1954; Chu and Hilaris 1961; Order et al 1968).
Advances in neuroimaging have facilitated earlier detection of smaller metastatic lesions, thereby allowing for earlier treatment than had previously been possible. Advances and refinements in neurosurgical techniques have also allowed for more aggressive resection of metastatic lesions while drastically decreasing surgical morbidity and mortality. In 1990, the value of surgical excision of a single brain metastasis was demonstrated in a landmark prospective, randomized controlled clinical trial. This study demonstrated improved survival for patients with a single brain metastasis who had surgical resection and WBRT, as compared with those patients treated with WBRT alone (Patchell et al 1990). Since the publication of this trial, additional studies have demonstrated the efficacy of surgical excision for select patients with multiple brain metastases (Bindal et al 1993; Andrews et al 1996). There is some evidence to suggest that total intracerebral tumor volume may be more important than the number of metastases (Petrovich et al 2002).
Surgical resection of brain metastases in modern neurosurgery typically utilizes state-of-the-art techniques including image-guidance or neuronavigation, intraoperative CT, MRI, or ultrasound imaging, electrophysiologic monitoring or mapping, operating microscope, and ultrasonic aspiration. The benefits of surgical resection include immediate decompression of critical structures, and relief of mass effect, as well as the opportunity to obtain tissue for pathologic and molecular diagnosis. Alternatively, a stereotactic brain biopsy may be performed in order to obtain tissue for pathology.
Whole brain radiotherapy (WBRT) consists of irradiating the entire brain, typically with 30 Gray (Gy) in 3 Gy fractions or 30 to 50 Gy in 2 to 2.5 Gy fractions. This radiation technique appears to be most effective for controlling many small (less than 0.5 cm), radiosensitive metastases, as well as metastases that are too small to be detected on standard contrast (gadolinium)-enhanced MR imaging (ie, micrometastases). As patients with brain metastases are surviving longer, the delayed cognitive impairment that often results from WBRT is becoming a more important consideration in treatment planning (Grandi et al 2012; Tallet et al 2012). Impairment typically occurs in a biphasic pattern, consisting of a transient subacute decline that peaks at 4 months postradiation, followed by a delayed irreversible impairment. Progressive white matter changes have been documented on serial MRI scans in patients receiving WBRT (Szerlip et al 2011).
Current techniques to mitigate neurocognitive decline due to WBRT include hippocampal avoidance WBRT (HA-WBRT) and prophylactic use of memantine, a NMDA antagonist (Wu et al 2012; Gondi et al 2014). The hippocampus is known to play a vital role in memory formation, learning, and spatial processing, and the neurons in this region of the brain are particularly vulnerable to radiation damage. NMDA rich neurons in the hippocampus are susceptible to radiation-induced overexcitation and toxicity. Consequently, memantine may prevent neuronal cell death from excitotoxicity. The recently presented results of the phase 3 NRG CC001 trial directly evaluating the efficacy of memantine and HA-WBRT versus memantine and traditional WBRT use in patients with brain metastases demonstrate superior neurocognitive outcomes in the investigational arm. Stereotactic radiosurgery (SRS) utilizes stereotactically directed convergent radiation beams that accurately and precisely deliver a high dose of radiation to the tumor. The major benefit of this technique is that the radiation dose rapidly falls off at the tumor margins, thereby sparing surrounding normal tissues from the detrimental effects of high dose radiation. Stereotactic radiosurgery can be accomplished with a modified linear accelerator, using multiple convergent arcs to reduce the radiation exposure outside of the target lesion; the CyberKnife uses a small linear accelerator mounted on a robotic arm, whereas the Gamma Knife employs fixed Cobalt 60 radiation sources focused on a central point. Advances in technology have allowed for more conformal treatment plans that are individually tailored to the size, shape, and location of the tumor, yet the radiation dose to surrounding brain tissue remains prohibitively high for lesions greater than 3 to 4 cm in diameter. A variation of stereotactic radiosurgery for treatment near vital structures (eg, optic nerves, chiasm, or brainstem) is fractionated stereotactic radiosurgery or stereotactic body radiotherapy (SBRT), in which the lesion is treated in up to 5 separate (usually daily or every other day) sessions (eg, 30 Gy divided over five 6-Gy fractions). This technique is particularly valuable for larger tumors or tumors in very close proximity to critical structures.
Stereotactic radiosurgery is often used as an adjunct to surgical resection, and in some cases, stereotactic radiosurgery is now the primary treatment modality (Petrovich et al 2002; Hasegawa et al 2003). Stereotactic radiosurgery can readily treat brain metastases (Bhatnagar et al 2006; Karlsson et al 2009; Grandhi et al 2012; Smith et al 2014), and the maximum number of lesions that can be effectively treated with stereotactic radiosurgery continues to increase as experience with this treatment modality increases and the evidence for the negative effects of WBRT continues to grow (Grandi et al 2012; Tallet et al 2012). In a study by Grandhi and colleagues, patients harboring more than 10 lesions have shown lengthy functional survival with stereotactic radiosurgery (Grandhi et al 2012). An observational study comparing the survival of patients having either 2 to 4 brain metastases or 5 to 10 metastases treated with stereotactic radiosurgery alone also showed that the outcome was not inferior in those patients with 5 to 10 metastases, supporting the use of stereotactic radiosurgery alone in patients with multiple lesions (Yamamoto et al 2014).
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