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COMMENTARY
Year : 2018  |  Volume : 66  |  Issue : 3  |  Page : 739-742

Brain metastasis and their management: A current perspective


1 Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow, Uttar Pradesh, India
2 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow, Uttar Pradesh, India

Date of Web Publication15-May-2018

Correspondence Address:
Dr. Kuntal Kanti Das
Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.232312

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How to cite this article:
Das KK, Jaiswal S. Brain metastasis and their management: A current perspective. Neurol India 2018;66:739-42

How to cite this URL:
Das KK, Jaiswal S. Brain metastasis and their management: A current perspective. Neurol India [serial online] 2018 [cited 2018 Dec 15];66:739-42. Available from: http://www.neurologyindia.com/text.asp?2018/66/3/739/232312




Brain metastasis (BM) remains a major source of morbidity and mortality in the cancer survivors. Owing to a combination of factors, their incidence seems to be on the rise all over the world. While earlier papers revealed rather conservative estimates (8.3 to 14.3 per 100,000 population), the current estimates indicate that nearly 45% of the cancer survivors go on to develop BM within 6 years of their primary diagnosis. It is estimated that nearly 2,00,000 people are diagnosed with BM in the United States every year.[1] The situation is not likely to be much different in our part of the world. Singh et al., have reported an incidence of 4.6% in the study in focus, which may not be the true reflection of the disease burden in this part of the world.[2]

All over the world, the three most common primary sites contributing metastatic deposits in the brain, in descending order, include the lungs, breasts and skin (melanomas).[3],[4] Singh et al., noted a higher incidence of gastrointestinal secondaries compared to melanomas in their study, which was unusual when compared to the published literature.[2] Does it really indicate that brain secondaries from melanomas are actually less common in South Eastern Asia? It may not necessarily be so. As these tumors are very well known to be radioresistant, their prognosis tends to be poor. Therefore, it has likely reflected in the authors' data as their center was a referral center for adjuvant therapy without having any neurosurgical services that would include a higher incidence of excisable brain metastasis usually coming under the purview of a neurosurgeon. On the other hand, colorectal secondaries are more likely to be subjected to postoperative radiotherapy.

Pathophysiologically, it is now understood that the cells destined to metastasize to the brain have different molecular signatures compared to the remaining cells in a given tumor (e.g., HOXB9 expression in lung cancer and NOTCH pathway expression in breast carcinoma).[5] These cells enter the circulation and after evading all the levels of resistance on their way, reach the brain parenchyma. Critical interaction with the blood–brain barrier (BBB), the glial cells and the local immune system as well as recruitment of vascular supply via various growth factors (e.g., vascular endothelial growth factor [VEGF]) lead to the eventual establishment of the metastatic deposit.[5] These pathways are being increasingly unraveled in recent translational research and are already being targeted in preclinical studies.

Metastatic deposits inside the brain have two basic features that often act as vantage points during their treatment. Firstly, these lesions tend to grow adjacent to the sulci at the cortex-white matter junction, rendering them accessible to surgical excision on most occasions. Secondly, metastatic lesions grow by expansion of the cell mass with resultant compression of the adjacent tissue, unlike malignant gliomas which tend to infiltrate. This rather circumscribed growth pattern allows supramaximal surgical excision on most occasions as well as effective utilization of stereotactic radiosurgery in a single/oligometastatic disease.

Interestingly, nearly 67% of the patients in this series had an occult primary at the time of evaluation. This incidence was much higher than the usually reported rate of 15-20% in the literature.[1],[4] The presence of an occult primary is a situation wherein the primary source of BM remains obscure despite exhaustive investigations. It is important, at this point, to be aware that many a times, the primary lesion eventually surfaces within a couple of months, a phenomenon known as metachronous presentation of BM. Thus, it is imperative to extensively investigate these patients with the investigations directed at the possible location of the primary, and to closely follow these patients to be able to detect a metachronous clinical presentation. A thorough clinical examination must be supplemented by a high resolution computed tomography (HRCT) of the chest, a mammography/ultrasound superadded on a magnetic resonance imaging of the breast, gastrointestinal endoscopy, etc. Functional scans like positron emission tomography (PET) and Tc99m bone scan should also be performed, although their sensitivity remains a matter of debate.

As far as the central nervous system (CNS) manifestations of systemic cancers are concerned, apart from the usual direct clinical manifestations like headache, vomiting, seizures and focal neurological dysfunction, one must be cognizant of certain unusual and indirect clinical manifestations as well. These include neurologic paraneoplastic syndromes (NPNS), various cerebrovascular syndromes, CNS infections from chemotherapy induced immunosuppression as well as the neurologic toxicities of systemic chemotherapy.[6] Out of these, NPNSs and cerebrovascular syndromes deserve a special mention here. NPNSs are typically subacute and cause progressive neurological impairment, particularly affecting multiple levels of the neuraxis. These syndromes represent immune mediated phenomena, and occasionally, a previous or a family history of other immunological conditions may be present in such cases. Examples include the Lambert Eaton syndrome associated with small cell lung carcinoma, the opsoclonus-myoclonus manifestation in a neuroblastoma, etc. Cerebrovascular syndromes include thrombotic, embolic or even hemorrhagic strokes. Intravascular invasion of tumor cells and a generalized procoagulant state generated by systemic cancers often lead to thrombosis of the smaller intracranial vessels. Rarely, there may be cerebral venous sinus thrombosis (CVST) from the same mechanism. Intracranial embolic strokes may result from associated opportunistic infections (bacterial) or more commonly from the non-infective cardiac vegetations of systemic tumors, known as non-bacterial thrombotic endocarditis (NBTE). The latter is more commonly seen with lung and mucin producing gastrointestinal tumors. Hemorrhagic transformation in BM may mimic hemorrhagic strokes and these are generally seen in secondaries from a melanoma, renal cell carcinoma or choriocarcinoma. Mycotic intracranial aneurysms resulting from systemic infections or angioinvasive opportunistic fungal (aspergillus) infection, may also result in hemorrhagic strokes. Sometimes, especially when associated with hematologic malignancies, a concomitant consumption coagulopathy may lead to intracranial hemorrhages.

A histopathological confirmation of the diagnosis is paramount to initiating radio-chemotherapy in BM. Moreover, the diagnosis based purely on neuroimaging has pitfalls in that 15-20% of these patients may have some other histological diagnosis! One of the daunting tasks for a pathologist dealing with a surgical specimen in which a BM is suspected, is to be able to predict the site of primary, i.e., in the patients where an occult primary exists. In this regard, immunohistochemistry (IHC) has an important role to play.[7] Perhaps the most important message emanating from the paper in focus, by Singh et al., pertains to this particular aspect. However, it must be remembered that IHC findings are generally similar in primary as well as the secondary tumors, and predicting the primary site may not be such a straight-forward job. Primary tumors from different organs may have similar morphology, e.g., the papillary architecture may arise from thyroid, lung, ovary, or kidney malignancies; and, glands/acini may be seen in adenocarcinoma arising from lung, thyroid, or the gastrointestinal tract. Sometimes, morphology of the primary tumor changes at the metastatic site. Moreover, a single IHC marker may be positive in more than one primary tumors. Hence, a panel of IHC markers along with a clinic-radiological correlation is recommended to assess the exact nature and origin of metastatic neoplasm, especially in the cases with an unknown primary [Table 1].
Table 1: Practical approach for IHC evaluation in brain metastases

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Before considering treatment for BM, it is imperative to determine their prognosis. This facilitates the choice of the most appropriate treatment modality that balances the durability of BM control with the adverse effects including the quality of life. Various scoring systems have been proposed to grade such patients to be able to predict the expected overall survival. These scoring systems take into account the patient's age, performance status (Karnofsky performance score), presence or absence of extracranial disease, as well as the status of the primary lesion. The recursive partitioning analysis (RPA), and more recently, disease specific graded prognostic assessment (GPA) were proposed by the Radiation Therapy Oncology Group (RTOG).[8] The GPA is more detailed, quantitative and objective of the two systems, although the two systems have not been compared in any randomized control trials yet.

The choices available for managing BMs include surgery, stereotactic radiosurgery (SRS), external beam radiotherapy (EBRT) and chemotherapy/molecular agents active against the primary tumor. The very aim of therapy directed at the BM (s) is to prevent neurological complications and resultant death. It is important to realize that the control of BM does not affect the over-all survival of these patients, which remains a direct function of the status of the systemic disease.[1],[4],[8]

Surgery plays a key role in the management of BM. There is level I evidence in favor of surgery combined with whole brain radiotherapy (WBRT) versus WBRT alone in solitary brain metastasis.[9],[10] However, the results of the solitary metastasis are much better than the single metastasis, indicating that the survival afforded by surgical excision of CM is offset by the progression of systemic disease. Apart from establishing the diagnosis, surgery has the benefit of reduction of mass effect produced by the tumor, of improving the local disease control and surgery can also potentiate the action of adjuvant radiation therapy. Typically, lesions larger than 3 cm in size, located in accessible areas, and causing mass effect, are subjected to surgical excision. Although the evidence is not as strong, surgical excision of up to 3 BM has been found to prolong local disease control in BM. Stereotactic biopsy (either frame-based or frame- less) plays an important role in establishing the diagnosis in deep-seated and small lesions. Surgical excision in BM generally attempts an en bloc and supramarginal tumor resection, whenever possible. Intraoperative image guidance, confocal microscopy, Raman spectroscopy, etc., can facilitate visualization of the tumor-brain interface and enhance the extent of tumor excision. Recently, minimally invasive methods like laser interstitial therapy and cryoablation have been used in small metastatic deposits detected on routine screening or at post-SRS recurrence.[8]

WBRT used to be the only treatment option for BM in the initial days. A combination of widespread recognition of their long-term side-effects as well as the emergence of SRS in the last two decades have restricted the widespread use of WBRT in BM today.[8] Three randomized controlled trials, namely the Japanese Radiation Oncology Study Group (JROSG) trial (2006), MD Anderson Cancer Center trial (2009) and European Organization for Research Treatment of Cancer (EORTC){2011} trials have demonstrated that the addition of WBRT after either surgery or SRS for an oligo-metastatic disease (1-4 metastasis) does not improve the overall survival, although local and distant relapses inside the brain are significantly lessened.[11],[12],[13] Subsequent analysis of these trials have identified certain patient subgroups, in whom improvement in the overall survival has been shown as well. WBRT is still used at centers where SRS is not available and as a palliative option for multiple BM in patients with a poor prognosis.

Stereotactic radiosurgery (SRS) has really changed the management paradigms of BM in the recent years. A high-dose focused radiation, a short treatment duration, as well as the lack of interruption of the systemic therapy (which is generally stopped during WBRT) are specific advantages of SRS. Usually, it is a single session therapy although the definition has recently been extended to 2 to 5 fractions. Lesions <3 cm in size (approximately 10 ml volume), located deep within the brain are ideal cases for SRS. The dosage applied is typically >18 Gy.[14] The effectiveness of SRS in sustained local disease control in single as well as multiple BM has been established in numerous randomized controlled trials. The American Society of Radiation Oncology (ASRO) guidelines recommend SRS as an alternative treatment to surgery for a single lesion <3 cm in size in good prognosis patients.[15] It also recommends an SRS boost after WBRT in good prognosis patients with multiple metastases to improve local control, reduce steroid usage as well as to improve the performance score. For breast and lung secondaries, 81-98% local control has been documented. The rates are 73-93% for melanoma and renal cell carcinoma, considered conventionally as being radio-resistant.[8]

Systemic therapy is largely ineffective in the majority of the BMs except those arising from radiosensitive primaries like lungs, breast, etc. Metastatic lesions will generally respond best to the agents effective against the primary cancer; however, the circulated cells may have substantial genetic differences from their primary tumor. Otherwise, empirically, certain agents with a good CNS penetration like topotecan, irinotecal, carboplatin and procarbazine may be used. Nevertheless, chemotherapy remains an effective treatment option for cranial secondaries arising from extracranial lymphoma, germ cell tumors, small cell lung cancer (SCLC) and breast carcinoma. With a far better understanding of the molecular biology of many systemic cancers, it has now been possible to utilize targeted therapies to treat these lesions, like dobrafenib, an anti-BRAF monoclonal antibody has shown promising results in a phase 3 trial for metastatic melanomas.[16]

Therefore, the outcome of patients with BM has improved drastically in the present scenario. Stereotactic radiosurgery has emerged as a dominant treatment option in the management of both single, as well as multiple BM. While systemic therapies are still largely ineffective in BM, a large body of preclinical research is underway at the moment, which is likely to impact the treatment paradigms for intracranial metastases in the near future.



 
  References Top

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Gavrilovic IT, Posner JB. Brain metastases: Epidemiology and pathophysiology. J Neurooncol. 2005;75:5-14.  Back to cited text no. 1
    
2.
Singh S, Amirtham U, Premalata CS, Lakshmaiah KC, Viswanath L, Rekha V. et al. Spectrum of metastatic neoplasms of the brain: A clinicopathological study in a tertiary care cancer centre. Neurol India 2018;66:733-8.  Back to cited text no. 2
    
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Barnholtz-Sloan JS1, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan Detroit cancer surveillance system. J Clin Oncol 2004;22:2865-72.  Back to cited text no. 3
    
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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;94:2698-705.  Back to cited text no. 4
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Seoane J, De Mattos-Arruda L Brain metastasis: new opportunities to tackle therapeutic resistance. Mol Oncol 2014;8:1120-31.  Back to cited text no. 5
    
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Khasraw M, Posner JB. Neurological complications of systemic cancer, Lancet Neurol 2010;9:1214-27.  Back to cited text no. 6
    
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Drlicek M, Bodenteich A, Urbanits S, Grisold W. Immunohistochemical panel of antibodies in the diagnosis of brain metastases of the unknown primary. Pathol Res Pract 2004;200:727-34.  Back to cited text no. 7
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Arvold ND, Lee EQ, Mehta MP, Margolin K, Alexander BM, Lin NU, et al. Updates in the management of brain metastases. Neuro-Oncology 2016;18:1043-65.  Back to cited text no. 8
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Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494-500.  Back to cited text no. 9
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Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: A randomized trial. JAMA. 1998;280:1485-9.  Back to cited text no. 10
    
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Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: A randomized controlled trial. JAMA 2006;295:2483-91.   Back to cited text no. 11
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Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: Results of the EORTC 22952-26001 study. J Clin Oncol 2011;29:134-41.   Back to cited text no. 12
    
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Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth FG, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol 2009;10:1037-44.   Back to cited text no. 13
    
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Lippitz B, Lindquist C, Paddick I, Peterson D, O'Neill K, Beaney R. Stereotactic radiosurgery in the treatment of brain metastases: The current evidence. Cancer Treatment Reviews 2014;40:48-59.  Back to cited text no. 14
    
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American Society for Radiation Oncology. 2014 Choosing Wisely List. Available from: https://www.astro.org/Patient-Care/ 17 1060 Downloaded from http://neuro-oncology.oxfordjournals.org/by guest on July 7, 2016 Patient-Education/2014-Choosing-Wisely-List/. [Last accessed on 2016 May 03].  Back to cited text no. 15
    
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Hauschild A, Grob JJ, Demidov LV, Jouary T, Jouary T, Gutzmer R, et al. Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358-65.  Back to cited text no. 16
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