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      Medical management of brain metastases

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          The development of brain metastases occurs in 10–20% of all patients with cancer. Brain metastases portend poor survival and contribute to increased cancer mortality and morbidity. Despite multimodal treatment options, which include surgery, radiotherapy, and chemotherapy, 5-year survival remains low. Besides, our current treatment modalities can have significant neurological comorbidities, which result in neurocognitive decline and a decrease in a patient’s quality of life. However, innovations in technology, improved understanding of tumor biology, and new therapeutic options have led to improved patient care. Novel approaches in radiotherapy are minimizing the neurocognitive decline while providing the same therapeutic benefit. In addition, advances in targeted therapies and immune checkpoint inhibitors are redefining the management of lung and melanoma brain metastases. Similar approaches to brain metastases from other primary tumors promise to lead to new and effective therapies. We are beginning to understand the appropriate combination of these novel approaches with our traditional treatment options. As advances in basic and translational science and innovative technologies enter clinical practice, the prognosis of patients with brain metastases will continue to improve.

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          Most cited references94

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          EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

          Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
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            Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System.

            Population-based estimates of the incidence of brain metastases are not generally available. The purpose of this study was to calculate population-based incidence proportions (IPs) of brain metastases from single primary lung, melanoma, breast, renal, or colorectal cancer. Patients diagnosed with single primary lung, melanoma, breast, renal, or colorectal cancer (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System (MDCSS) were used for analysis. IP of brain metastases by primary site and variable of interest (race, sex, age at diagnosis of primary cancer, and Surveillance, Epidemiology, and End Results [SEER] stage of primary cancer) was calculated with 95% CIs. Total IP percentage (IP%) of brain metastases was 9.6% for all primary sites combined, and highest for lung (19.9%), followed by melanoma (6.9%), renal (6.5%), breast (5.1%), and colorectal (1.8%) cancers. Racial differences were seen with African Americans demonstrating higher IP% of brain metastases compared with other racial groups for most primary sites. IP% was significantly higher for female patients with lung cancer, and significantly higher for male patients with melanoma. The highest IP% of brain metastases occurred at different ages at diagnoses: age 40 to 49 years for primary lung cancer; age 50 to 59 years for primary melanoma, renal, or colorectal cancers; and age 20 to 39 for primary breast cancer. IP% significantly increased as SEER stage of primary cancer advanced for all primary sites. Total IP% of brain metastases was lower than previously reported, and it varied by primary site, race, sex, age at diagnosis of primary cancer, and SEER stage of primary cancer.
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              Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.

              Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.
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                Author and article information

                Journal
                Neurooncol Adv
                Neurooncol Adv
                noa
                Neuro-oncology Advances
                Oxford University Press (US )
                2632-2498
                Jan-Dec 2020
                09 August 2020
                09 August 2020
                : 2
                : 1
                : vdaa015
                Affiliations
                Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic , Cleveland, Ohio, USA
                Author notes
                Corresponding Author: Manmeet Ahluwalia, MD, FACP, Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, S73, Cleveland, OH 44195, USA ( ahluwam@ 123456ccf.org ).
                Author information
                http://orcid.org/0000-0001-5654-0784
                Article
                vdaa015
                10.1093/noajnl/vdaa015
                7415253
                32793881
                75a7916d-a33c-47d7-bc24-a4e6cca73203
                © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 09 August 2020
                Page count
                Pages: 14
                Categories
                Reviews
                AcademicSubjects/MED00300
                AcademicSubjects/MED00310

                brain metastases,immunotherapy,radiation,surgery,targeted therapy

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