Management Of Brain Metastases Research Articles

From Patchell to Brown: An Evidence-Based Evolution of the Role of Radiotherapy on the Management of Brain Metastases

About 1,658,370 new cancer cases are expected to be diagnosed in the United States in 2015, and 589,430 Americans are expected to die of cancer. Despite those dreadful numbers, the 5-year survival rate for all cancers diagnosed in 2004 2010 was 68%, up from 49% in 1975 1977. The steady improvement in survival seen throughout those past 4 decades can be attributed to a combination of early diagnosis and better treatment modalities. Brain metastases occur in 20% 40% of patients with systemic cancer and are the most common type of intracranial tumor, outnumbering primary tumors by 10 to 1. They are multifocal in more than 70% of cases. Notwithstanding the improvements in survival in stage IV (metastatic) patients as a whole, the occurrence of brain metastases is often considered a sign of uncontrolled or treatment resistant disease and carries a dismal prognosis. As a case in point, the median overall survival is 1 2 months with corticosteroids, which can be extended to 6 months with whole brain radiation therapy (WBRT). The treatment algorithm for brain metastases typically involves some combination of surgical resection, radiotherapy, radiosurgery, and corticosteroids. With few exceptions, systemic therapies like chemotherapy are usually not an effective first-line treatment modality. The utility of the surgical management of single brain metastases was described by Patchell et al. in 1990. In this small, double-arm, randomized, prospective trial, 48 patients were randomized to either surgical removal of the brain tumor followed by WBRT (surgical group) or needle biopsy and WBRT (radiation group). Same-site recurrence was less frequent in the surgical group (20% vs. 52%). More importantly, the overall survival was significantly longer in the surgical group (median 40 weeks vs. 15 weeks in the radiation group) and those patients remained functionally independent longer (38 weeks vs. 8 weeks in the radiation group). When death from systemic causes was used as the survival end point, the differences between the surgical and radiation groups were not statistically significant. Twenty-five years after its publication, the first Patchell et al. randomized study remains one of the most cited articles on the theme, with more than 2100 indexed citations. Because most cases of brain metastases are multifocal, surgical resection is limited to only 10% 20% of the patients. In situations where surgical resection is not indicated or of limited benefit, WBRT has historically been the mainstay of treatment. The decision to use WBRT revolves around its impact on 3 interrelated components: 1) overall survival, 2) intracranial control, and 3) neurocognitive sequelae. While a large volume of retrospective reports support the effectiveness of WBRT on the management of brain metastases, there are no high-level

Chirurgie et radiothérapie des métastases cérébrales des carcinomes bronchiques non à petites cellules : quand et comment ?

Brain metastases are the first cause of intracranial malign tumor. Most of brain metastases are secondary to lung cancer. The management of brain metastases is becoming very challenging. For years the standard treatment has been whole brain radiation therapy alone, and the validity of this treatment alone is now under question for many patients because the role of stereotactic radiosurgery, surgery and novel targeted therapies has to be discussed in a multidisciplinary way, taking into account the intracranial and also the extra-cranial status. In 2014, the French neuro-oncology association (ANOCEF) established guidelines with a multidisciplinary approach.

Management of Brain Metastases in Patients With SCLC: Defining the Role for Stereotactic Radiosurgery

Management of Brain Metastases in Patients With SCLC: Defining the Role for Stereotactic Radiosurgery

Resection Followed by Involved-Field Fractionated Radiotherapy in the Management of Single Brain Metastasis.

We expanded upon our previous experience using involved-field fractionated radiotherapy (IFRT) as an alternative to whole brain radiotherapy or stereotactic radiosurgery for patients with surgically resected brain metastases (BM). All patients with single BM who underwent surgical resection followed by IFRT at our institution from 2006 to 2013 were evaluated. Local recurrence (LR)-free survival, distant failure (DF)-free survival, and overall survival (OS) were determined. Analyses were performed associating clinical variables with LR and DF. Salvage approaches and toxicity of treatment for each patient were also assessed. Median follow-up was 19.1 months. Fifty-six patients were treated with a median dose of 40.05 Gy/15 fractions with IFRT to the resection cavity. LR-free survival was 91.4%, DF-free survival was 68.4%, and OS was 77.7% at 12 months. No variables were associated with increased LR; however, melanoma histopathology and infratentorial location were associated with DF on multivariate analysis. LRs were salvaged in 5/8 patients, and DFs were salvaged in 24/29 patients. Two patients developed radionecrosis. Adjuvant IFRT is feasible and safe for well-selected patients with surgically resected single BM. Acceptable rates of local control and salvage of distal intracranial recurrences continue to be achieved with continued follow-up.

Brain metastases: advances over the decades.

The morbidity and mortality associated with metastatic disease to brain make this problem a formidable challenge faced by health care providers and caregivers. The aim of this review is to summarize management for patients with brain metastases with a particular focus on symptom management. A systematic review of the literature was performed. Outcomes of interest included survival, brain control (local in field and whole brain). In particular, symptom control (quality of life, neurological function and neurocognition) was examined. Steroids provide relief of symptoms due to intra-cerebral edema. The steroid of choice is dexamethasone. Anti-seizure medications should not be given as prophylaxis but instead be given for treatment of seizures. Depending on patient, tumour and treatment factors, management for brain metastases range from optimal supportive care including the use of steroids, whole brain radiotherapy (WBRT), radiosurgery, surgery alone or in combination. Surgery or radiosurgery improves survival for selected patients with single brain metastasis as compared to WBRT alone. Ongoing research topics include focal postoperative cavity radiation, focal fractionated regimens, molecular targeted therapies, chemoprevention of brain metastases and neurocognitive protection (such as neuro-protective drugs and radiation techniques such as hippocampal sparing). The management of brain metastases has evolved over the decades. Other than survival and brain control (local in-field and whole brain), the outcomes of quality of life and neurocognition are becoming increasingly important.

Management of brain metastasis with magnetic resonance imaging and stereotactic irradiation attenuated benefits of prophylactic cranial irradiation in patients with limited-stage small cell lung cancer.

BackgroundMagnetic resonance imaging (MRI) enables a more sensitive detection of brain metastasis and stereotactic irradiation (SRI) efficiently controls brain metastasis. In limited-stage small cell lung cancer (LS-SCLC), prophylactic cranial irradiation (PCI) in patients with good responses to initial treatment is recommended based on the survival benefit shown in previous clinical trials. However, none of these trials evaluated PCI effects using the management of brain metastasis with MRI or SRI. This study aimed to determine the effects of MRI and SRI on the benefits of PCI in patients with LS-SCLC.MethodsThe clinical records of pathologically proven SCLC from January 2006 to June 2013 in facilities equipped with or had access to SRI in Japan were retrospectively reviewed. Patients with LS-SCLC and complete or good partial responses after initial treatment were included in the study and analyzed by the Kaplan-Meier method.ResultsOf 418 patients with SCLC, 124 met criteria and were divided into patients receiving PCI (PCI group; n = 29) and those without PCI (non-PCI groups; n = 95). At baseline, ratios of patients with stage III were significantly advantageous for the non-PCI group, although younger age and high ratios of complete response and MRI confirmed absence of brain metastasis were advantageous for the PCI group. Neither median survival times (25 vs. 34 months; p = 0.256) nor cumulative incidence of brain metastasis during 2 years (45.5 vs. 30.8 %; p = 0.313) significantly differed between the two groups. Moreover, these factors did not significantly differ among patients with stage III disease (25 vs. 26 months; p = 0.680, 42.3 vs. 52.3 %; p = 0.458, respectively).ConclusionPCI may be less beneficial in patients with LS-SCLC if the management with MRI and SRI is available.

Current Perspectives in the Management of Brain Metastases.

Brain metastases (BMs) are diagnosed in 10%-40% of all patients with cancer, and the incidence continues to increase along with the number of long-term survivors. When BMs occur, they are often associated with a myriad of symptoms, including neurologic dysfunction and functional decline; both are difficult to manage and can be distressing for patients and their caregivers. Although clinically significant findings have not kept up with the rapid pace of scientific breakthroughs in understanding the mechanisms of BMs, novel approaches that affect the prognosis of patients with BMs have been introduced in clinical practice. At a Glance • Screening for brain metastases (BMs) is not routinely performed in patients with no neurologic symptoms. However, screening is indicated in lung cancer and possibly in the context of high-risk cancers. • Individual differences in patients warrant a personalized approach in the management of BMs. • Whole brain radiation therapy and steroids are considered to be the cornerstones of treatment for BMs.

Intérêt de la documentation biologique de la maladie métastatique cérébrale dans le cancer du sein : à propos d’un cas

Breast cancer, after lung cancer, is the second major cause of brain metastases. In breast cancer, the prognosis is closely linked to the molecular subtype of the primary tumor. Targeted therapies, with or without cytotoxic treatment, have significantly modified overall survival in these patients. We report, the case of a patient suffering from breast cancer with brain metastasis in whom the biological documentation of the metastatic disease permitted to tailor the systemic treatment. Analysis of the surgical specimen revealed an immunohistochemical HER2 positive staining, which was not found in the primary tumor and therefore warranted trastuzumab administration. Another interesting insight based on this case report was to underline the phenotypic heterogeneity of the metastatic disease and its potential dynamic course as illustrated by the dissociated response to trastuzumab on body TEP-TDM in this particular patient. This case report also highlights the new place of the neurosurgeon in brain metastases management, not only as a participant in local treatment but also as a physician who is in fact involved in the delineation of the global oncological strategy in these patients as well as medical oncologists and radiation oncologists.

Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis

Small cell lung cancer is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing to brain early. However, the cellular and molecular basis is poorly known. Here, we provided evidence to reveal the role of annexin A1 in small cell lung cancer metastasis to brain. Firstly, the elevated annexin A1 serum levels in small cell lung cancer patients were associated with brain metastasis. The levels of annexin A1 were also upregulated in NCI-H446 cells, a small cell lung cancer cell line, upon migration into the mice brain. More interestingly, annexin A1 was secreted by NCI-H446 cells in a time-dependent manner when co-culturing with human brain microvascular endothelial cells, which was identified with the detections of annexin A1 in the co-cultured cellular supernatants by ELISA and western blot. Further results showed that blockage of annexin A1 in the co-cultured cellular supernatants using a neutralized antibody significantly inhibited NCI-H446 cells adhesion to brain endothelium and its transendothelial migration. Conversely, the addition of Ac2-26, an annexin A1 mimic peptide, enhanced these effects. Furthermore, knockdown of annexin A1 in NCI-H446 cells prevented its transendothelial migration in vitro and metastasis to mice brain in vivo. Our data showed that small cell lung cancer cell in brain microvasculature microenvironment could express much more annexin A1 and release it outside, which facilitated small cell lung cancer cell to gain malignant properties of entry into brain. These findings provided a potential target for the management of SCLC brain metastasis.

Surgery in neuro-oncolgy with a focus on stereotactic radiosurgery.

Veronica Chiang is jointly appointed as Associate Professor in Neurosurgery and Therapeutic Radiology at the Yale School of Medicine. Dr Chiang became the Medical Director of the Yale New Haven Hospital Gamma Knife Center in 2006 where currently over 300 patients are treated each year. She is predominantly interested in the management of brain metastases and now works closely with Medical Oncologists, Radiation Oncologists, Pathologists and Radiologists in the development of new treatment paradigms for patients with brain metastases as well as understanding the effects of these treatments on the normal brain.

Systemic therapies for melanoma brain metastases: which drug for whom and when?

Melanoma brain metastases are common, difficult to treat, and are associated with a poor prognosis. Historically, due to the poor activity of chemotherapeutic agents in melanoma, the management of brain metastases was centred on local treatments such as surgery, stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) depending on the clinical presentation. New systemic therapies have now evolved; kinase inhibitors targeting BRAF mutated melanoma cells and activating checkpoint inhibitors that activate an immune anti-tumour response, resulting in significantly improved survival and quality of life for patients with metastatic melanoma and these drugs have demonstrated activity in melanoma brain metastases. As the landscape shifts to incorporate these new systemic agents with the available local therapies, further research into using appropriate combinations or sequences of various treatments, especially for active or progressing melanoma brain metastasis, is required. This review will examine the evidence for systemic therapies in patients with active melanoma brain metastasis (untreated or treated and progressed) and highlight active and evolving clinical trials in this challenging field.

Whole-brain radiotherapy and stereotactic radiosurgery in brain metastases: what is the evidence?

The overall local treatment paradigm of brain metastases, which includes whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS), continues to evolve. Local therapies play an important role in the management of brain metastases. The choice of local therapy depends on factors that involve the patient (performance status, expected survival, and age), the prior treatment history, and the tumor (type and subtype, number, size, location of metastases, and extracranial disease status). Multidisciplinary collaboration is required to facilitate an individualized plan to improve the outcome of disease in patients with this life-limiting complication. There has been concern about the neurocognitive effects of WBRT. A number of approaches that mitigate cognitive dysfunction, such as pharmacologic intervention (memantine) or a hippocampal-sparing strategy, have been studied in a prospective manner with WBRT. Although there has been an increase in the use of SRS in the management of brain metastases in recent years, WBRT retains an important therapeutic role.

Management and prognosis of patients with brain metastasis from gestational trophoblastic neoplasia: a 24-year experience in Peking union medical college hospital.

BackgroundThe optimal treatment for patients with brain metastasis from gestational trophoblastic neoplasia (GTN) has not been established. This study aims to investigate the clinical characteristics and the management of brain metastasis from GTN in relation to patients’ outcomes.MethodsWe retrospectively investigated 109 GTN patients with brain metastasis treated at Peking Union Medical College Hospital from January 1990 to December 2013. Patients mainly received multiagent chemotherapy with florouracil or floxuridine, dactinomycin, etoposide, and vincristine (FAEV) combined with intrathecal methotrexate with or without surgery.ResultsIn the 109 patients, sixty-two (56.1%) patients presented for primary therapy and 47 patients had failed chemotherapy elsewhere. Eight early demise patients who died before or during first cycle of chemotherapy were excluded from analysis. The median follow-up time was 47 months (range 9–180 months). The overall 5-year survival rate (OS) was 71.1%, while the OS rate for patients receiving primary chemotherapy in our hospital was 85.5%, and this fell to 51.9% in patients with failure multidrug chemotherapy elsewhere. Multivariate analysis demonstrated that International Federation of Gynecology and Obstetrics (FIGO) scores over 12 (Hazard ratio-HR 1.279, 95% CI 1.061-1.541, P = 0.010), failure of previous multidrug chemotherapy (HR 3.177, 95% CI 1.277-7.908, P = 0.013), and concurrent renal metastasis (HR 2.654, 95% CI 1.125-6.261, P = 0.026) were the risk factors of overall survival in patients with brain metastases from GTN.ConclusionsPatients with brain metastasis from GTN have favorable outcome by multidrug chemotherapy and adjuvant therapies. Nevertheless, the prognosis is poor if the patients had previous multidrug failure chemotherapy history, concomitant with renal metastasis, or FIGO score over 12. Initial treatment with FAEV combined with intrathecal methotrexate chemotherapy can bring bright prospect to patients with brain metastases from GTN.

EP-1299: Simultaneous integrated boost, a novel approach in the management of brain metastases

EP-1299: Simultaneous integrated boost, a novel approach in the management of brain metastases

Contemporary Review of the Management of Brain Metastasis with Radiation

Brain metastases are an important cause of morbidity and mortality, afflicting approximately 200,000 Americans annually. The prognosis for these patients is poor, with median survivals typically measured in months. In this review article, we present the standard treatment approaches with whole brain radiation and as well as novel approaches in the prevention of neurocognitive deficits.

Traitement systémique des métastases cérébrales de mélanome

Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) – ipilimumab – or BRAF (serine/threonine-protein kinase B-raf) inhibitors – vemurafenib, dabrafenib – has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).

Stratégie globale de prise en charge des métastases cérébrales : une approche multidisciplinaire

Brain metastases management has evolved over the last fifteen years and may use varying strategies, including more or less aggressive treatments, sometimes combined, leading to an improvement in patient's survival and quality of life. The therapeutic decision is subject to a multidisciplinary analysis, taking into account established prognostic factors including patient's general condition, extracerebral disease status and clinical and radiological presentation of lesions. In this article, we propose a management strategy based on the state of current knowledge and available therapeutic resources.

Targeted and Immunotherapeutic Approaches in Brain Metastases

Brain metastases are a common and devastating complication of cancer. The approach to the management of brain metastases is often multidisciplinary and includes surgery, whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and systemic therapeutic agents. Until recently, systemic therapy has had a limited role in the management of brain metastases because of a lack of activity, challenges of blood-brain barrier penetration, the heterogeneous patient population, and a heavily pretreated patient population. Advances in the understanding of the biology of brain metastases and molecularly defined disease subsets have facilitated an emerging role of novel therapeutic agents, including targeted therapies and immunotherapy, in the management of brain metastases.

Clinicopathological Evaluation and Prognostic Analysis in Breast Cancer Patients with Brain Metastasis

Background: Brain metastases are diagnosed in 5% - 15% of patients with breast cancer. Clinical management of brain metastases appears to be crucial in improving the prognosis of patients with breast cancer that has metastasized to the brain. However, few studies have investigated whether treatment of metastatic brain tumors would lead to improved prognosis. Methods: A total of 41 breast cancer patients whose tumors metastasized to the brain and who were diagnosed and treated at our hospital were enrolled. This study was conducted to determine the characteristics of brain metastases and to identify the factors that may affect the treatment and prognosis of patients with brain metastases. Results: There were more patients with HER2 and triple negative subtypes than of the luminal subtype. The median time from the initiation of breast cancer treatment to the onset of brain metastasis was 31 months (range, 7 - 134 months). Significantly greater disease-specific survival (DSS) was observed in patients who had a performance status of 0 - 2 at the time of diagnosis of metastatic brain tumors than those with a performance status of 3 - 4 (p = 0.04). DSS was also significantly greater in patients who underwent surgery to remove brain metastases and in patients treated with systemic therapy (p = 0.0007 and 0.0001, respectively). Conclusions: It may be possible to improve the prognosis of patients with brain metastases if lesions are detected early enough when the patients’ performance status is still good. In order for these findings to be definitive, however, results of future prospective studies are eagerly awaited.

Research progress of targeted therapy in non-small cell lung cancer brain metastases

肺癌最常见的远处转移部位之一是脑部，肺癌脑转移的发生率为20%-65%，是脑转移性肿瘤中最常见的类型，同时也是肺癌死亡率高居不下的原因之一。分子靶向治疗已成为肺癌治疗的重要手段，分子靶向药物也成为继全脑放疗、立体定向放疗和化疗之后肺癌脑转移新的治疗方法。目前，对脑转移的非小细胞肺癌患者应用靶向药物治疗的研究也越来越多，其安全性和有效性是研究的重点。本文就靶向药物治疗非小细胞肺癌脑转移的研究进展做一综述。