No reliable estimates are available on the incidence in cancer patients. This information is valuable for planning patient care and developing measures that may prevent or decrease the likelihood of metastatic brain disease.
Brain metastases are the most common cause of malignant brain tumours in adults. Of the nearly 1·5 million patients in the USA who received a primary diagnosis of cancer in 2007, about 70 000 of these primary diagnoses are estimated to eventually relapse in the brain 1) 2)).
Between 20% and 40% of all patients with metastatic cancer will have brain metastases at autopsy 3).
Rates of CNS involvement in metastatic cancer are believed to be increasing, possibly owing to better control of systemic disease with novel chemotherapies or improved metastasis detection.
However, controversies exist regarding demographic and clinical profile of brain metastases.
Analysis from the Kentucky and Alberta cancer registries similarly demonstrated the aggressive nature of lung cancer and its propensity for BM at initial presentation. Besides widespread organ involvement, no synchronous organ site predicted BM in lung cancer. BM is a common and important clinical outcome, and use of registry data is becoming more available 4).
Despite the frequency of brain metastases, prospective trials in this patient population are limited, and the criteria used to assess response and progression in the CNS are heterogeneous 5).
From different cancers.
The majority of brain metastases originate from primary cancers in the lung (40–50%) or breast (15–25%), or from melanoma (5–20%) 9)
They are common in elderly population and mostly due to primary lung. Adenocarcinoma was the most common histology of primary. Majority of lesions has been observed at parietal lobe 10).
Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown.
Brastianos et al. detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases 11).
CDH2, KIFC1, and FALZ3
HDAC3, JAG2, NUMB, APH1B, HES4, and PSEN1
Presenting symptoms include headache (49%), focal weakness (30%), mental disturbances (32%), gait ataxia (21%), seizures (18%), speech difficulty (12%), visual disturbance (6%), sensory disturbance (6%), and limb ataxia (6%) 12).
Neuropsychological testing demonstrates cognitive impairment in 65% of patients with brain metastases 13) 14) , which might be a result of destruction or displacement of brain tissue by the expanding tumor, peritumoral edema leading to further disruption of surrounding white matter tracts, increased intracranial pressure, and/or vascular compromise.
Magnetic resonance imaging with contrast enhancement is the imaging procedure of choice to diagnose and characterize brain metastases. Multiple lesions with marked vasogenic edema and mass effect are typically seen in patients with brain metastases. The classical appearance of a metastasis is a solid enhancing mass with well-defined margins and extensive edema. Occasionally, central necrosis produces a ring enhancing mass.
The MR assessment should include T1-weighted images with and without enhancement and T2/FLAIR images. They usually appear as multiple lesions with nodular or annular enhancement and are surrounded by edema. They are hypervascularized and have no restriction of their diffusion coefficient in their necrotic area and contain lipids on 1H spectroscopy. Metastases can be distinguished from primary tumors by the lack of malignant cell infiltration around the tumor 15).
The main differential diagnosis includes primary tumours, abscesses, vascular and inflammatory lesions.
The management of patients with brain metastases has become a major issue due to the increasing frequency and complexity of the diagnostic and therapeutic approaches. In 2014, the European Association of NeuroOncology (EANO) created a multidisciplinary Task Force to draw evidence-based guidelines for patients with brain metastases from solid tumors. Soffietti et al. present these guidelines, which provide a consensus review of evidence and recommendations for diagnosis by neuroimaging and neuropathology, staging, prognostic factors, and different treatment options. Specifically, they addressed options such as surgery, stereotactic radiosurgery/stereotactic fractionated radiotherapy, whole-brain radiotherapy, chemotherapy and targeted therapy (with particular attention to brain metastases from non-small cell lung cancer, melanoma and breast and renal cancer), and supportive care 16).
With the development of therapies that improve extracranial disease control and increase long-term survival of patients with metastatic cancer, effective treatment of brain metastases while minimizing toxicities is becoming increasingly important. An expanding arsenal that includes surgical resection, whole brain radiation therapy, radiosurgery, and targeted systemic therapy provides multiple treatment options. However, significant controversies still exist surrounding appropriate use of each modality in various clinical scenarios and patient populations in the context of cancer care strategies that control systemic disease for increasingly longer periods of time. While whole brain radiotherapy alone is still a reasonable and standard option for patients with multiple metastases, several randomized trials have now revealed that survival is maintained in patients treated with radiosurgery or surgery alone, without upfront whole brain radiotherapy, for up to four brain metastases. Indeed, recent data even suggest that patients with up to 10 metastases can be treated with radiosurgery alone without a survival detriment. In an era of dramatic advances in targeted and immune therapies that control systemic disease and improve survival but may not penetrate the brain, more consideration should be given to brain metastasis-directed treatments that minimize long-term neurocognitive deficits, while keeping in mind that salvage brain therapies will likely be more frequently required. Less toxic therapies now also allow for concurrent delivery of systemic therapy with radiosurgery to brain metastases, such that treatment of both extracranial and intracranial disease can be expedited, and potential synergies between radiotherapy and agents with central nervous system penetration can be harnessed 17).
Historically, overall survival after diagnosis is poor; however, since 1980s, improved systemic disease therapies and multimodality brain metastasis treatment have substantially increased survival. This increase in the quantity of life after diagnosis allows clinicians to minimize morbidity and focus on the patient’s quality of life. Choosing an appropriate personalized treatment plan for patients with brain metastasis maximizes survival and minimizes morbidity from unnecessary or futile treatments. The wide variety of tumor types, treatment strategies, and constant innovations within the field requires close collaboration among neurosurgeons, medical oncologists, radiation oncologists, and other specialists. Current treatment paradigms for brain metastases employ several treatment modalities, including open surgical resection, Gamma Knife or CyberKnife stereotactic radiosurgery, focused external beam radiotherapy, whole-brain radiotherapy (WBRT), traditional chemotherapy, and newer targeted biological agents personalized for tumor type.
Advances in intraoperative surgical technology (i.e., fluorescence, confocal microscopy, and brachytherapy) hold promise for improved outcomes for brain metastasis resection. The future of brain metastasis management is predicated on personalized therapy targeted to specific tumor molecular pathways, such as those involved in blood–brain barrier transgression, cell–cell adhesion, and angiogenesis. Brain metastases are often biologically distinct lesions compared to the primary tumor. Personalized therapies should therefore be chosen on the basis of brain metastasis tissue whenever available. The multidisciplinary management of patients with brain metastases by neurosurgeons, medical oncologists, and radiation oncologists is essential as therapies become increasingly complex and individualized 18).
Neurosurgical resection and whole brain radiation therapy (WBRT) are accepted treatments for single and oligometastatic cancer to the brain.
Local radiotherapy as adjuvant treatment to surgical resection of brain metastases is associated with an increased rate of development of new distant metastases and leptomeningeal disease compared with WBRT, but not with recurrence at the resection site or of unresected lesions treated with radiation 24).
The neurosurgical treatment of patients with metastatic cancer is an integral component of multimodality therapy for brain and spinal metastases. Survival benefit has been demonstrated for the addition of open surgery as well as the use of stereotactic radiosurgery (SRS) to whole-brain radiation therapy for treatment of patients with isolated cranial metastases compared with whole-brain radiation therapy alone. New clinical trials that directly compare open surgical procedures with SRS are underway 25).
see En bloc resection.
To avoid the decline in neurocognitive function (NCF) linked to WBRT, the authors conducted a prospective, multicenter, phase 2 study to determine whether surgery and carmustine wafers (CW), while deferring WBRT, could preserve NCF and achieve local control (LC).
NCF and LC were measured in 59 patients who underwent resection and received CW for a single (83%) or dominant (oligometastatic, 2 to 3 lesions) metastasis and received stereotactic radiosurgery (SRS) for tiny nodules not treated with resection plus CW. Preservation of NCF was defined as an improvement or a decline ≤ 1 standard deviation from baseline in 3 domains: memory, executive function, and fine motor skills, evaluated at 2-month intervals.
Significant improvements in executive function and memory occurred throughout the 1-year follow-up. Preservation or improvement of NCF occurred in all 3 domains for the majority of patients at each of the 2-month intervals. NCF declined in only 1 patient. The chemowafers were well tolerated, and serious adverse events were reversible. There was local recurrence in 28% of the patients at 1-year follow-up.
The rate of LC (78%) was comparable to historic rates of surgery with WBRT and superior to reports of WBRT alone. For patients who undergo resection for symptomatic or large-volume metastasis or for tissue diagnosis, the addition of CW can be considered as an option 26).
Brain metastases are associated with a dismal prognosis. Treatment options for patients with brain metastases (BM) have limited efficacy and the mortality rate is virtually 100%.
Overall prognosis depends on age, extent and activity of the systemic disease, number of brain metastases and performance status. In about half of the patients, especially those with widespread and uncontrolled systemic malignancy, death is heavily related to extra-neural lesions, and treatment of cerebral disease doesn't significantly improve survival.
In such patients the aim is to improve or stabilize the neurological deficit and maintain quality of life. Corticosteroids and whole-brain radiotherapy usually fulfill this purpose. By contrast, patients with limited number of brain metastases, good performance status and controlled or limited systemic disease, may benefit from aggressive treatment as both quality of life and survival are primarily related to treatment of brain lesions.
Strong positive prognostic factors include good functional status, age <65 years, no sites of metastasis outside of the central nervous system (CNS), controlled primary tumor 27), the presence of a single metastasis in the brain, long interval from primary diagnosis to brain relapse, and certain cancer subtypes such as HER2 positive breast cancer brain metastases and EGFR-mutant non-small-cell lung cancer (NSCLC) 28) 29) 30)
It is difficult to differentiate local tumour recurrences from radiation induced-changes in case of suspicious contrast enhancement. New advanced MRI techniques (perfusion and spectrometry) and amino acid positron-emission tomography (PET) allow to be more accurate and could avoid a stereotactic biopsy for histological assessment, the only reliable but invasive method.
The multimodal MRI has greatly contributed to refine the differential diagnosis between tumour recurrence and radionecrosis, which remains difficult. The FDG PET is helpful, in favour of the diagnosis of local tumour recurrence when a hypermetabolic lesion is found. Others tracers (such as carbon 11 or a fluoride isotope) deserve interest but are not available in all centres. Stereotactic biopsy should be discussed if any doubt remains 32).