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Brain metastases


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).

This heterogeneity largely stems from the recognition that existing criteria sets, such as RECIST 6) 7).



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).

Genes involved

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




Clinical Presentation

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).

Differential diagnosis

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).

That means that the treatment of brain metastases is multidisciplinary with radiation forming the cornerstone 19) 20).

Neurosurgical resection and whole brain radiation therapy (WBRT) are accepted treatments for single and oligometastatic cancer to the brain.

The combination of radiotherapy and chemotherapy improves response rate and/or progression-free survival in some studies, but not overall survival 21). 22) 23).

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).

Surgical treatment

Carmustine Wafer

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).

Stereotactic Radiosurgery


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)

Recursive partitioning analysis class, under the category “Brain Cancer” 31).


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).

An increase in FLAIR signal of the fluid within the resection cavity might be a highly specific and early sign of local tumor recurrence/tumor progression also for brain metastases. 33).

FG Davis, TA Dolecek, BJ McCarthy, JL Villano Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data Neuro Oncol, 14 (2012), pp. 1171–1177
American Cancer Society Cancer Facts & FiguresAmerican Cancer Society, Atlanta, GA (2007
Sawaya R, Bindal RK, Lang FF, Abi-Said D. 2nd ed. New York: Churchill Livingstone; 2001. Metastatic brain tumors.
Villano JL, Durbin EB, Normandeau C, Thakkar JP, Moirangthem V, Davis FG. Incidence of brain metastasis at initial presentation of lung cancer. Neuro Oncol. 2014 Jun 2. pii: nou099. [Epub ahead of print] PubMed PMID: 24891450.
NU Lin, EQ Lee, H Aoyama, et al. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group Lancet Oncol, 14 (2013), pp. e396–e406
EA Eisenhauer, P Therasse, J Bogaerts, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer, 45 (2009), pp. 228–247
P Therasse, SG Arbuck, EA Eisenhauer, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst, 92 (2000), pp. 205–216
8) , 9)
Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94:2698–2705.
Saha A, Ghosh SK, Roy C, Choudhury KB, Chakrabarty B, Sarkar R. Demographic and clinical profile of patients with brain metastases: A retrospective study. Asian J Neurosurg. 2013 Jul;8(3):157-61. doi: 10.4103/1793-5482.121688. PubMed PMID: 24403959.
Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, Van Allen EM, Lawrence MS, Horowitz PM, Cibulskis K, Ligon KL, Tabernero J, Seoane J, Martinez-Saez E, Curry WT, Dunn IF, Paek SH, Park SH, McKenna A, Chevalier A, Rosenberg M, Barker FG 2nd, Gill CM, Van Hummelen P, Thorner AR, Johnson BE, Hoang MP, Choueiri TK, Signoretti S, Sougnez C, Rabin MS, Lin NU, Winer EP, Stemmer-Rachamimov A, Meyerson M, Garraway L, Gabriel S, Lander ES, Beroukhim R, Batchelor TT, Baselga J, Louis DN, Getz G, Hahn WC. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov. 2015 Sep 26. [Epub ahead of print] PubMed PMID: 26410082.
Posner JB. Neurologic Complications of Cancer. Vol. 37. Philadelphia: Davis FA; 1995. Paraneoplastic Syndromes; p. 311.
Chang EL, et al. A pilot study of neurocognitive function in patients with one to three new brain metastases initially treated with stereotactic radiosurgery alone. Neurosurgery. 2007;60:277–283.
Mehta MP, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol. 2003;21:2529–2536
Grand S, Pasteris C, Attye A, Le Bas JF, Krainik A. The different faces of central nervous system metastases. Diagn Interv Imaging. 2014 Oct;95(10):917-31. doi: 10.1016/j.diii.2014.06.014. Review. PubMed PMID: 25023732.
Soffietti R, Abacioglu U, Baumert B, Combs SE, Kinhult S, Kros JM, Marosi C, Metellus P, Radbruch A, Villa Freixa SS, Brada M, Carapella CM, Preusser M, Le Rhun E, Rudà R, Tonn JC, Weber DC, Weller M. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol. 2017 Feb 1;19(2):162-174. doi: 10.1093/neuonc/now241. PubMed PMID: 28391295.
Shen CJ, Lim M, Kleinberg LR. Controversies in the Therapy of Brain Metastases: Shifting Paradigms in an Era of Effective Systemic Therapy and Longer-Term Survivorship. Curr Treat Options Oncol. 2016 Sep;17(9):46. Review. PubMed PMID: 27447703.
Hardesty DA, Nakaji P. The Current and Future Treatment of Brain Metastases. Front Surg. 2016 May 25;3:30. doi: 10.3389/fsurg.2016.00030. eCollection 2016. Review. PubMed PMID: 27252942; PubMed Central PMCID: PMC4879329.
Chang JE, Robins HI, Mehta MP. Therapeutic advances in the treatment of brain metastases. Clin Adv Hematol Oncol. 2007;5:54–64.
Mintz A, Perry J, Spithoff K, Chambers A, Laperriere N. Management of single brain metastasis: a practice guideline. Curr Oncol. 2007 Aug;14(4):131-43. PubMed PMID: 17710205; PubMed Central PMCID: PMC1948870.
Antonadou D, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol. 2002;20:3644–3650.
Robinet G, et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) Protocol 95–1. Ann Oncol. 2001;12:59–67.
Verger E, et al. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int J Radiat Oncol Biol Phys. 2005;61:185–191.
Hsieh J, Elson P, Otvos B, Rose J, Loftus C, Rahmathulla G, Angelov L, Barnett GH, Weil RJ, Vogelbaum MA. Tumor Progression in Patients Receiving Adjuvant Whole-Brain Radiotherapy vs Localized Radiotherapy After Surgical Resection of Brain Metastases. Neurosurgery. 2015 Apr;76(4):411-20. doi: 10.1227/NEU.0000000000000626. PubMed PMID: 25599198.
Claus EB. Neurosurgical management of metastases in the central nervous system. Nat Rev Clin Oncol. 2011 Dec 6;9(2):79-86. doi: 10.1038/nrclinonc.2011.179. Review. PubMed PMID: 22143137.
Brem S, Meyers CA, Palmer G, Booth-Jones M, Jain S, Ewend MG. Preservation of neurocognitive function and local control of 1 to 3 brain metastases treated with surgery and carmustine wafers. Cancer. 2013 Nov 1;119(21):3830-8. doi: 10.1002/cncr.28307. Epub 2013 Aug 23. PubMed PMID: 24037801.
Gaspar L, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37:745–751.
Melisko ME, Moore DH, Sneed PK, De Franco J, Rugo HS. Brain metastases in breast cancer: clinical and pathologic characteristics associated with improvements in survival. J Neurooncol. 2008;88:359–365.
Eichler AF, et al. Survival in patients with brain metastases from breast cancer: the importance of HER-2 status. Cancer. 2008;112:2359–2367.
Eichler AF, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol. 2010;12:1193–1199.
Barnholtz-Sloan JS, Yu C, Sloan AE, Vengoechea J, Wang M, Dignam JJ, Vogelbaum MA, Sperduto PW, Mehta MP, Machtay M, Kattan MW. A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro Oncol. 2012 Jul;14(7):910-8. doi: 10.1093/neuonc/nos087. Epub 2012 Apr 27. PubMed PMID: 22544733; PubMed Central PMCID: PMC3379797.
Patsouris A, Augereau P, Tanguy JY, Morel O, Menei P, Rousseau A, Paumier A. [Differentiation from local tumour recurrence and radionecrosis after stereotactic radiosurgery for treatment of brain metastasis.]. Cancer Radiother. 2014 Jan 13. pii: S1278-3218(13)00444-7. doi: 10.1016/j.canrad.2013.10.013. [Epub ahead of print] French. PubMed PMID: 24433952.
Bette S, Gempt J, Wiestler B, Huber T, Specht H, Meyer B, Zimmer C, Kirschke JS, Boeckh-Behrens T. Increase in FLAIR Signal of the Fluid Within the Resection Cavity as Early Recurrence Marker: Also Valid for Brain Metastases? Rofo. 2017 Jan;189(1):63-70. doi: 10.1055/s-0042-119686. PubMed PMID: 28002859.
brain_metastases.txt · Last modified: 2017/09/03 13:39 by administrador