|Year : 2017 | Volume
| Issue : 2 | Page : 121-127
Management of lung cancer brain metastasis: An overview
Himanshu Srivastava1, Preety Negi2, Pamela Alice Kingsley2, Jaineet Sachdeva2
1 Department of Radiation Oncology, Capitol Hospital, Jalandhar, Punjab, India
2 Department of Radiation Oncology, Christian Medical College and Hospital, Ludhiana, Punjab, India
|Date of Web Publication||2-Feb-2018|
Dr. Himanshu Srivastava
Department of Radiation Oncology, Capitol Hospital, Jalandhar - 144 012, Punjab
Source of Support: None, Conflict of Interest: None
With the improvements in systemic treatment for lung cancer, distant metastasis to sanctuary sites such as brain has become an increasingly more important issue. The management of these patients consists of supportive care and disease-directed treatment. Combined modality treatment (surgical resection or radiosurgery, followed by whole brain radiotherapy) of brain metastases has greatly improved the local control of disease in patients with single lesion, good functional performance status, and controlled extracranial disease as demonstrated in prospective randomized studies. For patients with multiple brain metastases, conventional fractionated whole brain radiotherapy continues to be a standard and efficacious treatment. At present, experience with the use of molecularly targeted tyrosine kinase inhibitors in nonsmall cell lung cancer patients with activating mutations in the epidermal growth factor receptor gene and anaplastic lymphoma kinase gene is growing. However, their effectiveness in patients with brain metastases is not well established. In the arena of targeted therapies, vascular endothelial growth factor pathway inhibitors such as bevacizumab have shown some activity in brain metastases. Further prospective studies are necessary to facilitate selection of patient subpopulation for targeted agents in future studies.
Keywords: Bevacizumab, brain neoplasms, combined modality therapy, epidermal growth factor receptor, nonsmall cell lung carcinoma, receptor protein tyrosine kinase
|How to cite this article:|
Srivastava H, Negi P, Kingsley PA, Sachdeva J. Management of lung cancer brain metastasis: An overview. Asian J Oncol 2017;3:121-7
|How to cite this URL:|
Srivastava H, Negi P, Kingsley PA, Sachdeva J. Management of lung cancer brain metastasis: An overview. Asian J Oncol [serial online] 2017 [cited 2018 May 21];3:121-7. Available from: http://www.asjo.in/text.asp?2017/3/2/121/224656
| Introduction|| |
Lung cancer remains the most common cause of cancer-related deaths in men worldwide. Out of the estimated 1.8 million new cases in 2012 (12.9% of the total), 58% occurred in the less developed regions with the highest estimated age-standardized incidence rates in Central and Eastern Europe (53.5/100,000) and Eastern Asia (50.4/100,000). In India, lung cancer constitutes 6.9% of all new cancer cases and 9.3% of all cancer-related deaths in both sexes. Lung carcinomas have been classified based on histopathological subtypes into small cell lung cancer (SCLC) and non-SCLC (NSCLC). Brain metastasis is one of the most important causes of treatment failure in patients with lung cancer. Approximately 10% of lung cancer patients present with brain metastasis at diagnosis and an estimated 40% will eventually develop brain metastasis during the course of the disease. Most of which occurs within 2 years with a median survival of 4–5 months., Keeping the increasing incidence and mortality associated with lung cancer brain metastasis (LCBM), we undertook this review to summarize the experience till date with respect to current treatment options and future novel approaches for the treatment of LCBM.
| Brain Metastasis in Small Cell Lung Cancer|| |
SCLC is neuroendocrine carcinoma accounting for approximately 10%–15% of lung cancer. The Veterans Administration Lung Cancer Study Group staged SCLC into limited (stage) disease (LD) or extensive (stage) disease (ED). Characteristic features of SCLC includes its aggressive behavior, rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy (CT) and radiation therapy (RT), and frequent association with distinct paraneoplastic syndromes., Without treatment, SCLC has the most aggressive clinical course of all histopathological types. Around two-thirds of all SCLC patients are diagnosed with ED, with metastasis commonly observed in the contralateral lung, liver, brain, and bones. In spite of the late detection of SCLC, a good initial response to CT and RT is observed in the majority of the patients. Unfortunately, even with this good initial response, the 5-year survival rate remains low at <7% overall, and most patients survive less than a year after diagnosis., Brain metastasis has been reported as a common event in SCLC and is considered a major clinical challenge. The increasing incidence of brain metastasis is directly related to patients surviving long enough after a primary cancer diagnosis to experience brain metastasis due to the improvements in the treatment of systemic disease.
| Brain Metastasis in Nonsmall Cell Lung Cancer|| |
NSCLC comprises several subclasses that include adenocarcinomas, squamous cell carcinomas, and large cell carcinomas constituting for approximately 80%–85% of lung cancer. The molecular targeted agents that inhibit epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) are approved for the treatment of NSCLC harboring genetic alterations in the genes encoding these proteins. Although the management of NSCLC patients has improved over time, due to the development of these molecular targeted agents with a better knowledge of prognostic factors, brain metastases still remain a common and lethal complication for these patients. In particular, this increased incidence of brain metastases has been attributed to: (1) the routine use of magnetic resonance imaging for staging purposes, even in patients with metastatic NSCLC, resulting in the identification of small asymptomatic lesions that would otherwise have gone unnoticed. (2) With the availability of more effective systemic therapy for patients with resected NSCLC and locally advanced NSCLC, the brain as a single site or as the first site of relapse is becoming more common.,, About 7%–10% of NSCLC patients present with brain metastasis at the time of initial diagnosis,, and approximately 25%–30% of newly diagnosed NSCLC patients develop brain metastasis at some point during their illness. The overall survival (OS) time for NSCLC patients with brain metastasis is <3–6 months when left untreated.
| Management of Lung Cancer Brain Metastasis|| |
In general, the initial management and prognosis of patients with brain metastasis depends on age, performance status, control of primary tumor, extent of extracranial disease, number of brain metastases, aggressive treatment modalities such as surgery or radiosurgery, and biomarkers such as expression levels of vascular endothelial growth factor (VEGF), cyclooxygenase-2, EGFR overexpression, and EGFR mutations. The treatment options for patients with LCBM are limited including surgical resection, whole brain RT (WBRT), stereotactic radiosurgery (SRS) alone, and potentially, systemic or targeted therapy, based on the above-mentioned factors.
| Medical Treatment|| |
Medical management of brain metastasis is considered an essential component requiring a prompt intervention to minimize progressive neurologic injury. Early integration of palliative care has demonstrated improvement in quality of life and mood, with improved survival despite less aggressive end-of-life treatment. In addition, patients with brain metastasis need supportive medications such as corticosteroids and anticonvulsants. Corticosteroids are vital for the improvement of symptoms by decreasing capillary permeability, thereby reducing intracranial edema. A systematic review by Ryken et al. has made the following recommendations:
- If corticosteroids are given, dexamethasone is the best choice
- Starting doses of 4–8 mg of dexamethasone should be given for temporary relief of symptoms related to increased intracranial pressure. In more severe cases where symptoms suggest impending herniation, doses of 16 mg/day or more may be considered
- There is insufficient evidence to guide treatment recommendations for asymptomatic brain metastasis.
Anticonvulsants are clearly known to impact negatively on quality of life and neurocognition. A systematic review on the role of prophylactic anticonvulsants in the management of brain metastasis found only one trial stratifying patients by metastasis versus primary pathology. This study reported a Level 3 recommendation of not to use routine prophylactic anticonvulsants, explained by the fact that anticonvulsant use can have significant adverse effects and by the lack of evidence suggesting any benefit from the prophylactic use of anticonvulsants for patients with brain metastasis. The key conclusion from these guidelines recommends that in view of the lack of a clear and robust benefit from the routine prophylactic use of anticonvulsants, they should be avoided.
Careful attention should be paid with regard to concurrent anticonvulsant medications when administering systemic therapy to patients with brain metastasis. The pharmacokinetic interactions between various chemotherapeutic agents and enzyme-inducing antiepileptic drugs including phenytoin, carbamazepine, and phenobarbital reduce the overall systemic exposure responsible for increased metabolism of chemotherapeutic agents leading to worsened clinical outcome., As levetiracetam is not an enzyme inducer, it is an attractive anticonvulsant in this setting.
| Radiation Therapy|| |
WBRT is the most widely accepted treatment for patients with brain metastasis. The rationale for this treatment approach is based on the presumption that micrometastatic deposits of tumor cells are present elsewhere in the brain. WBRT palliates the associated neurological symptoms and may prevent the growth of new metastases. There are no randomized, controlled clinical trials establishing a survival benefit from WBRT in NSCLC patients. In view of neurotoxic risks associated with WBRT and ability of SRS in very efficiently controlling few metastases, there is growing reliance on SRS for patients who have a limited number of brain metastases (usually 1–3)., However, WBRT still holds an important therapeutic role because of the easy availability and cost-effectiveness.
There are no randomized trials comparing SRS with traditional surgical resection. Surgical resection is recommended mainly for patients with a single brain metastasis in an accessible location, especially when the tumor size is large and causing a considerable mass effect or obstructive hydrocephalus. Surgery is also favored in patients with good performance status, who are functionally independent, and in whom systemic disease is limited or absent. In a systematic review of studies on managing single brain metastasis in various types of cancer, Gaspar et al. found that the combination of surgical resection plus WBRT was superior to either approach alone in patients with good performance status and who had few sites of extracranial disease. A low quality evidence regarding the addition of upfront WBRT to surgery or to SRS in decreasing any intracranial disease progression at 1 year has been provided by Cochrane review. The debate over whether to use SRS or WBRT as frontline treatment for brain metastasis still continues. Multiple randomized controlled trials failed to show OS benefit of adding WBRT to SRS.,, The NCCN guidelines for treating a single brain metastasis in NSCLC recommend surgery followed by WBRT or SRS, SRS followed by WBRT, or SRS alone, depending on the individual patient.
Whole brain radiotherapy is generally the standard of care in patients with multiple brain metastases, as it addresses both macroscopic and microscopic disease. WBRT has resulted in an improvement in symptoms in 64%–85% of patients., The role of SRS in multiple brain metastases, especially those with ≥4 tumors, remains controversial. The literature is emerging, and the limited evidence suggests that the local control benefit is independent of the number of metastases, and that patients with more than four brain metastases have similar OS compared to those with 2–4 lesions.,
Till date, there has been no consensus on the optimal dose and fractionation schedule for WBRT. Eight randomized controlled trials comparing the standard dose schedule (30 Gy divided into 10 fractions) with altered dose schedules on patients with brain metastases from various primary cancers including NSCLC reported no significant differences in OS and symptom control. A total of 30 Gy in ten fractions continue to be the standard for a vast majority of patients. A shorter fractionation scheme of 20 Gy in five fractions should be considered in CT refractory patients.
| Role of Prophylactic Cranial Irradiation in Small Cell Lung Cancer and Nonsmall Cell Lung Cancer|| |
Prophylactic cranial irradiation (PCI) was first tested for patients with SCLC in the 1970s following the recognition that the blood–brain barrier (BBB) appeared to restrict the penetration of most chemotherapeutics into the brain leaving it as a sanctuary site for relapse. A meta-analysis of five randomized controlled trials compared brain metastasis incidence and OS between PCI and no PCI in patients with SCLC. The results indicated that PCI decreases brain metastasis incidence and improves survival in SCLC patients. This systematic review suggested that PCI should be considered a part of standard care for all patients with SCLC who have a good response to initial CT. At present, the standard therapy for LD-SCLC is concurrent chemoradiotherapy and PCI for those who achieve complete response or good partial response with initial therapy, whereas the standard therapy for ED-SCLC is CT only. A Japanese Phase III study failed to confirm the usefulness of PCI for patients with ED-SCLC. In the 2014 edition of the Guidelines for the Treatment of Lung Cancer from the Japan Lung Cancer Society, use of PCI for patients with ED-SCLC has been changed from “recommended” to “not recommended,” and the guidelines only recommend PCI for patients with LD-SCLC who achieve complete response after initial treatment (Grade A recommendation) and patients with ED-SCLC who achieve complete response after initial treatment (Grade B recommendation) indicating appropriate selection of patients for PCI of paramount importance. A population-based analysis on the role of PCI among NSCLC patients at higher risk of brain metastasis (<60 years, adenocarcinoma, or stage IIIB) suggested no OS benefit of PCI even among high-risk patients.
| Systemic Chemotherapy|| |
Systemic CT is not routinely used in the treatment of LCBM as the large, hydrophilic molecules cannot penetrate the BBB and due to the presence of drug efflux mechanisms. In view of the dismal prognosis leading to exclusion of these patients in clinical trials, we are left with limited data on the efficacy of chemotherapeutic agents. Edelman et al. reported similar outcomes with regard to OS and median survival in patients receiving CT with a slight trend favoring patients without brain metastasis. In a meta-analysis of six randomized controlled trials involving 910 participants of LCBM, the results indicated that CT concurrent with WBRT was more effective at improving response rate than WBRT alone, but it did not improve median survival time or time of neurological progression. Since most of the studies included in the meta-analysis were retrospective or single arm-study and limited randomized controlled trials, the role of CT in LCBM remains controversial with no proven survival benefit.
The most extensively studied chemotherapeutic drugs with WBRT are temozolomide (TMZ) and the radiation sensitizer, motexafin gadolinium. Recent studies have raised concerns of worse outcomes with the combination of TMZ and WBRT in NSCLC patients. In the RT Oncology Group 0302 study, patients in the WBRT/SRS plus TMZ arm experienced shorter survival compared with those receiving WBRT/SRS alone (6.3 vs. 13.4 months) with increased toxicity. None of the other agents have shown evidence of significant improvement in response rate or survival. At present, concurrent CT with WBRT is not indicated outside of the context of a clinical trial.
| Role of Targeted Therapy|| |
Molecular targeted tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have proven to be effective in patients with activating mutations in the EGFR gene and chromosomal rearrangements involving the ALK gene. Despite their efficacy in systemic disease control, their effectiveness in patients with brain metastasis is not well established since data on the use of erlotinib or gefitinib are available from retrospective and nonrandomized studies with a limited number of patients., A Chinese study of 136 NSCLC patients with resected brain metastasis identified an EGFR mutation in 57% of the brain metastases, with a concordance rate of 93.3% in the EGFR mutation status between the primary tumor and brain metastasis. This suggested that the primary tumor EGFR status is a very good surrogate for EGFR mutation status of the brain metastasis. There is mounting evidence that treatment with TKIs results in high response rates (70%–89%), increased OS and progression-free survival (PFS) (12.9–19.8 months and 6.6–23.3 months, respectively) demonstrating an improved clinical outcome in selected populations of EGFR-mutated NSCLC patients with brain metastasis., Therefore, EGFR and ALK-TKIs are among valid options for patients with asymptomatic brain metastases from NSCLC, especially those with EGFR-activating mutations or harboring ALK-rearrangement.
For EGFR-mutant NSCLC patients with asymptomatic brain metastasis who do not require urgent symptom relief, the proper treatment schedule is not well established. In a retrospective study on patients with asymptomatic brain metastasis without prior TKI treatment, first-line brain RT failed to improve long-term survival in TKI-naive EGFR mutant NSCLC patients with asymptomatic brain metastases.
The question of whether erlotinib or gefitinib can delay or obviate the need for brain radiation appears quite appealing. To answer this, a meta-analysis on EGFR-mutant NSCLC patients with brain metastasis was undertaken. The authors reported improved PFS and OS with the use of upfront cranial RT although with more neurological adverse effects than with TKIs alone. This meta-analysis provided evidence, albeit of low quality, that upfront cranial RT may improve intracranial disease control and survival outcomes compared with TKIs alone. Negative results were reported recently with the use of upfront EGFR-TKIs, with the deferral of SRS or WBRT resulting in inferior OS in patients with EGFR-mutant NSCLC who develop brain metastasis. Similarly, no significant difference in OS was reported in 110 patients with EGFR-mutant lung adenocarcinoma subjected to erlotinib versus RT for brain metastasis (median, 35 vs. 26 months; P = 0.62). However, this study underscored the role of WBRT in producing durable intracranial disease control in comparison with erlotinib. The results of above-mentioned studies suggest that local therapy may still be important for the treatment of brain metastases in patients with EGFR mutations.
Another issue of major importance is whether WBRT enhances the activity of EGFR inhibitors by, for example, disrupting the BBB and thus allowing a higher drug concentration to be achieved in brain metastasis. An intracerebral response rate of 75%–89% versus 84% has been reported in patients treated with EGFR-TKI alone and on combining EGFR-TKI with WBRT, respectively. This response rate was considerably higher as compared to what was expected from standard approaches such as CT and WBRT alone. However, this hypothesis has yet to be confirmed by sound data in prospective trials in the future.
Alterations in the ALK gene occur in 2%–7% of NSCLC patients and confer sensitivity to selective TKIs. Crizotinib is the first ALK inhibitor approved for the treatment of patients with metastatic NSCLC whose tumors harbor ALK rearrangement. However, it is important to note that patients develop resistance to crizotinib because of the weak penetration of the BBB by this drug. Although EGFR-TKIs produce lower drug concentrations in cerebrospinal fluid than in plasma, they achieve higher levels relative to crizotinib. Keeping the data till date in mind, it is suggested that crizotinib may not be the best ALK inhibitor for patients with brain metastases. However, promising responses in the central nervous system (CNS) in crizotinib-resistant brain metastases have been seen with second-generation ALK inhibitor, alectinib. Future studies are needed to clarify optimal sequencing of the above-mentioned TKIs in patients with CNS disease and whether these will be effective and safe in multimodality therapies such as in combination with radiation. Furthermore, a study evaluating immunotherapy in CNS metastases from NSCLC is underway (clinicaltrials.gov identifier: NCT02085070).
Another targeted approach studied in the treatment of brain metastases with NSCLC is the use of bevacizumab (BVZ), a recombinant humanized monoclonal antibody that obstructs VEGF pathway. Despite its extensive employment in the treatment of lung cancer, its role in LCBM is very limited. This is because of the exclusion of patients with brain metastases from BVZ clinical trials after the occurrence of a fatal cerebral hemorrhage in the Phase I study. However, the brain metastases as an exclusion criteria contradiction were removed after the retrospective analysis of clinical trial data suggested an equal risk of intracranial bleeding in patients with brain metastases treated with or without BVZ therapy., BVZ administration to NSCLC patients with symptomatic brain lesions, who were not suitable candidates for a specific local therapy, the PFS and OS data were very encouraging with symptomatic benefit due to BVZ's high capacity to provide a long-lasting decrease in perilesional edema. The results so far have suggested that a BVZ-based regimen is capable of eliciting an intracranial response and might offer an alternative treatment option for patients with brain metastases from NSCLC. There still remain several unanswered questions in view of the lack of prospectively conducted trials of BVZ in these patients.
| Conclusions|| |
With the advances in the management of lung cancer and better survival, more patients are likely to develop brain metastases. These patients have poor median survival, and more effective therapies are urgently required. The goal of treatment for these patients is longer survival with improved quality of life and preservation of neurocognitive function. PCI for patients without detectable brain metastases decreases the frequency of subsequent intracranial relapse and improves survival for patients with LD-SCLC. There is no proven role of PCI for patients with locally advanced NSCLC, not even among patients at higher risk of brain metastases. Local RT is still an important component of treatment for brain metastases in NSCLC patients with EGFR and ALK mutations. Current research is focused on various novel treatment approaches including the use of targeted therapies, using targeted therapy concurrent with radiation, and finally utilizing immunotherapy in patients with LCBM.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al
. GLOBOCON 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://www.globocan.iarc.fr
. [Last accessed on 2014 Jan 21].
Indian Council of Medical Research; 2013. National Cancer Registry Programme. Three Year Report of Population Based Cancer Registries: 2009-2011. Available from: http://www.ncrpindia.org
. [Last accessed on 2014 Jan 21].
Schuette W. Treatment of brain metastases from lung cancer: Chemotherapy. Lung Cancer 2004;45 Suppl 2:S253-7.
Robnett TJ, Machtay M, Stevenson JP, Algazy KM, Hahn SM. Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma. J Clin Oncol 2001;19:1344-9.
Zhang W, Jiang W, Luan L, Wang L, Zheng X, Wang G. Prophylactic cranial irradiation for patients with small-cell lung cancer: A systematic review of the literature with meta-analysis. BMC Cancer 2014;14:793.
Boffetta P, Trichopoulos D. Cancer of the lung, larynx, and pleura. In: Adami H, Hunter D, Trichopoulos D, editors. Textbook of Cancer Epidemiology. 2nd
ed. New York: Oxford University Press; 2008. p. 349-67.
Krug LM, Kris MG, Rosenzweig K, Travis WD. Cancer of the lung. In: DeVita VT Jr., Hellman S, Rosenberg SA, editors. Cancer: Principle and Practice of Oncology. 8th
ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2008. p. 947-66.
Lekic M, Kovac V, Triller N, Knez L, Sadikov A, Cufer T. Outcome of small cell lung cancer (SCLC) patients with brain metastases in a routine clinical setting. Radiol Oncol 2012;46:54-9.
Kalemkerian GP, Akerley W, Bogner P, Borghaei H, Chow LQ, Downey RJ, et al.
Small cell lung cancer. J Natl Compr Canc Netw 2013;11:78-98.
Semenova EA, Nagel R, Berns A. Origins, genetic landscape, and emerging therapies of small cell lung cancer. Genes Dev 2015;29:1447-62.
Byers LA, Rudin CM. Small cell lung cancer: Where do we go from here? Cancer 2015;121:664-72.
Schneider BJ, Kalemkerian GP. Personalized therapy of small cell lung cancer. Adv Exp Med Biol 2016;890:149-74.
Ricciardi S, de Marinis F. Multimodality management of non-small cell lung cancer patients with brain metastases. Curr Opin Oncol 2010;22:86-93.
Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24:2137-50.
Thomas A, Liu SV, Subramaniam DS, Giaccone G. Refining the treatment of NSCLC according to histological and molecular subtypes. Nat Rev Clin Oncol 2015;12:511-26.
Owen S, Souhami L. The management of brain metastases in non-small cell lung cancer. Front Oncol 2014;4:248.
Seute T, Leffers P, Wilmink JT, ten Velde GP, Twijnstra A. Response of asymptomatic brain metastases from small-cell lung cancer to systemic first-line chemotherapy. J Clin Oncol 2006;24:2079-83.
Chen AM, Jahan TM, Jablons DM, Garcia J, Larson DA. Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall-cell lung cancer: Clinical implications for the subsequent management of the brain. Cancer 2007;109:1668-75.
Cox JD, Scott CB, Byhardt RW, Emami B, Russell AH, Fu KK, et al.
Addition of chemotherapy to radiation therapy alters failure patterns by cell type within non-small cell carcinoma of lung (NSCCL): Analysis of radiation therapy oncology group (RTOG) trials. Int J Radiat Oncol Biol Phys 1999;43:505-9.
Louie AV, Rodrigues G, Yaremko B, Yu E, Dar AR, Dingle B, et al.
Management and prognosis in synchronous solitary resected brain metastasis from non-small-cell lung cancer. Clin Lung Cancer 2009;10:174-9.
Robinet G, Barlesi F, Gervais R, Lena H, Hureaux J, Berard H, et al
. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small cell lung cancer with measurable asymptomatic inoperable brain metastases: A multicentre phase II trial (GFPC 07-01). J Clin Oncol 2010;28:7595.
Berger LA, Riesenberg H, Bokemeyer C, Atanackovic D. CNS metastases in non-small-cell lung cancer: Current role of EGFR-TKI therapy and future perspectives. Lung Cancer 2013;80:242-8.
Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, et al.
Summary report on the graded prognostic assessment: An accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012;30:419-25.
Sullivan FJ. Palliative radiotherapy. In: Pass HI, Mitchell JB, Johnson DH, editors. Lung Cancer: Principles and Practice. 2nd
ed. Philadelphia: Lippincott Williams and Wilkins; 2000. p. 1006-23.
Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al.
Early palliative care for patients with metastatic non-small-cell lung cancer. N
Engl J Med 2010;363:733-42.
Ryken TC, McDermott M, Robinson PD, Ammirati M, Andrews DW, Asher AL, et al.
The role of steroids in the management of brain metastases: A systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:103-14.
Mikkelsen T, Paleologos NA, Robinson PD, Ammirati M, Andrews DW, Asher AL, et al.
The role of prophylactic anticonvulsants in the management of brain metastases: A systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:97-102.
Yap KY, Chui WK, Chan A. Drug interactions between chemotherapeutic regimens and antiepileptics. Clin Ther 2008;30:1385-407.
Oberndorfer S, Piribauer M, Marosi C, Lahrmann H, Hitzenberger P, Grisold W. P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neurooncol 2005;72:255-60.
Fonkem E, Bricker P, Mungall D, Aceves J, Ebwe E, Tang W, et al.
The role of levetiracetam in treatment of seizures in brain tumor patients. Front Neurol 2013;4:153.
Mulvenna PM, Nankivell MG, Barton R, Faivre-Finn C, Wilson P, Moore B, et al
. Whole brain radiotherapy for brain metastases from non-small lung cancer: Quality of life (QoL) and overall survival (OS) results from the UK Medical Research Council QUARTZ randomized clinical trial (ISRCTN 3826061). J Clin Oncol 2015;33:8005. [ASCO abstract 8005].
Mehta MP. The controversy surrounding the use of whole-brain radiotherapy in brain metastases patients. Neuro Oncol 2015;17:919-23.
Khalsa SS, Chinn M, Krucoff M, Sherman JH. The role of stereotactic radiosurgery for multiple brain metastases in stable systemic disease: A review of the literature. Acta Neurochir (Wien) 2013;155:1321-7.
Kalkanis SN, Kondziolka D, Gaspar LE, Burri SH, Asher AL, Cobbs CS, et al.
The role of surgical resection in the management of newly diagnosed brain metastases: A systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:33-43.
Gaspar LE, Mehta MP, Patchell RA, Burri SH, Robinson PD, Morris RE, et al.
The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: A systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:17-32.
Soon YY, Tham IW, Lim KH, Koh WY, Lu JJ. Surgery or radiosurgery plus whole brain radiotherapy versus surgery or radiosurgery alone for brain metastases. Cochrane Database Syst Rev 2014;3:CD009454.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-small Cell Lung Cancer. Version 3. 2016.
Sahgal A, Aoyama H, Kocher M, Neupane B, Collette S, Tago M, et al.
Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: Individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2015;91:710-7.
Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, et al.
Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2012;4:CD003869.
Akhtar MS, Kousar F, Fatmi S, Jabeen K, Akhtar K. Quality of life and symptoms control in brain metastasis after palliative whole brain radiotherapy using two different protocols. J Coll Physicians Surg Pak 2012;22:311-6.
Lam TC, Sahgal A, Chang EL, Lo SS. Stereotactic radiosurgery for multiple brain metastases. Expert Rev Anticancer Ther 2014;14:1153-72.
Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al.
Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): A multi-institutional prospective observational study. Lancet Oncol 2014;15:387-95.
Schild SE, Foster NR, Meyers JP, Ross HJ, Stella PJ, Garces YI, et al.
Prophylactic cranial irradiation in small-cell lung cancer: Findings from a North Central Cancer Treatment Group Pooled Analysis. Ann Oncol 2012;23:2919-24.
Nosaki K, Seto T. The role of radiotherapy in the treatment of small-cell lung cancer. Curr Treat Options Oncol 2015;16:56.
Seto T, Takahashi T, Yamanaka T, Nokihara H, Saka H, Nishio M, et al
. Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial. J Clin Oncol 2014;32:7503.
Park HS, Decker RH, Wilson LD, Yu JB. Prophylactic cranial irradiation for patients with locally advanced non-small-cell lung cancer at high risk for brain metastases. Clin Lung Cancer 2015;16:292-7.
Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: Establishing a treatment paradigm. J Clin Oncol 2007;25:2306-12.
Edelman MJ, Belani CP, Socinski MA, Ansari RH, Obasaju CK, Chen R, et al.
Outcomes associated with brain metastases in a three-arm phase III trial of gemcitabine-containing regimens versus paclitaxel plus carboplatin for advanced non-small cell lung cancer. J Thorac Oncol 2010;5:110-6.
Qin H, Pan F, Li J, Zhang X, Liang H, Ruan Z. Whole brain radiotherapy plus concurrent chemotherapy in non-small cell lung cancer patients with brain metastases: A meta-analysis. PLoS One 2014;9:e111475.
Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, et al.
Aphase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys 2013;85:1312-8.
Baik CS, Chamberlain MC, Chow LQ. Targeted therapy for brain metastases in EGFR-mutated and ALK-rearranged non-small-cell lung cancer. J Thorac Oncol 2015;10:1268-78.
Karachaliou N, Rosell R. Treatment of brain metastases in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations: The role of EGFR tyrosine kinase inhibitors. Ann Palliat Med 2013;2:114-7.
Luo D, Ye X, Hu Z, Peng K, Song Y, Yin X, et al.
EGFR mutation status and its impact on survival of Chinese non-small cell lung cancer patients with brain metastases. Tumour Biol 2014;35:2437-44.
Li Z, Guo H. The retrospective analysis of the frequency of EGFR mutations and efficacy of gefitinib in NSCLC patients with brain metastasis. J Clin Oncol 2011;29:e18065.
Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C, et al.
Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer 2009;65:351-4.
Dempke WC, Edvardsen K, Lu S, Reinmuth N, Reck M, Inoue A. Brain metastases in NSCLC - Are TKIs changing the treatment strategy? Anticancer Res 2015;35:5797-806.
Liu S, Qiu B, Chen L, Wang F, Liang Y, Cai P, et al.
Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: A retrospective clinical study. Radiat Oncol 2015;10:118.
Soon YY, Leong CN, Koh WY, Tham IW. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: A systematic review and meta-analysis. Radiother Oncol 2015;114:167-72.
Magnuson WJ, Yeung JT, Guillod PD, Gettinger SN, Yu JB, Chiang VL. Impact of deferring radiation therapy in patients with epidermal growth factor receptor-mutant non-small cell lung cancer who develop brain metastases. Int J Radiat Oncol Biol Phys 2016;95:673-9.
Gerber NK, Yamada Y, Rimner A, Shi W, Riely GJ, Beal K, et al.
Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys 2014;89:322-9.
Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al.
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N
Engl J Med 2010;363:1693-703.
Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, et al.
clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol 2015;33:1881-8.
Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al.
Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: A phase II global study. J Clin Oncol 2016;34:661-8.
Gordon MS, Margolin K, Talpaz M, Sledge GW Jr., Holmgren E, Benjamin R, et al.
Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001;19:843-50.
Schettino C, Bareschino MA, Rossi A, Maione P, Sacco PC, Colantuoni G, et al.
Targeting angiogenesis for treatment of NSCLC brain metastases. Curr Cancer Drug Targets 2012;12:289-99.
Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res 2010;16:269-78.
Zustovich F, Ferro A, Lombardi G, Farina P, Zagonel V. Bevacizumab-based therapy for patients with brain metastases from non-small-cell lung cancer: Preliminary results. Chemotherapy 2014;60:294-9.
De Braganca KC, Janjigian YY, Azzoli CG, Kris MG, Pietanza MC, Nolan CP, et al.
Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer. J Neurooncol 2010;100:443-7.