Presence Of Brain Metastases Research Articles

Clinical Analysis of Icotinib on Beneficiary of Advanced Non-small Cell Lung Cancer with EGFR Common Mutation

背景与目的靶向治疗已经成为晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）治疗中不可或缺的重要手段，表皮生长因子受体（epithelial growth factor receptor, EGFR）的酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）可显著延长晚期携带EGFR基因突变肺癌患者生存期。埃克替尼是我国第一个拥有自主知识产权的EGFR-TKI。本研究旨在探讨埃克替尼治疗EGFR敏感突变的晚期NSCLC获益患者的临床特点，对获益患者[无进展生存时间（progression-free survival, PFS）≥6个月]进行回顾性资料收集并分析相关影响因素。方法收集2011年9月1日-2015年9月30日浙江省肿瘤医院经埃克替尼片治疗的231例EGFR敏感突变的晚期NSCLC获益患者的生存情况。结果经埃克替尼治疗后，一线治疗组1年获益率达67.9%，二线及以上组为53.6%，具有统计学意义（P=0.027）；一线治疗组2年获益率对比二线及以上组亦有统计学差异（18.7%和9.3%，P=0.047）。一线患者和二线及以上患者的中位PFS分别为16.7个月和12.4个月，且差异具有统计学意义（P=0.006）。其中有无脑转移（P=0.010）、埃克替尼治疗时机（P=0.001）、美国东部肿瘤协作组（Eastern Cooperative Oncology Group, ECOG）评分（P=0.001）为影响预后的主要因素。主要不良反应为皮疹51例（22.1%），腹泻27例（11.7%）。结论埃克替尼是EGFR基因敏感突变的晚期NSCLC患者有效的治疗方案，其优势人群除无脑转移者及ECOG评分好的患者外，一线治疗患者疗效明显优于二线及以上者。敏感突变患者采用埃克替尼可得到较好的临床获益，并具有较好的耐受性。

MP03-08 COMPREHENSIVE ANALYSIS AND VALIDATION OF CONTEMPORARY SURVIVAL PROGNOSTICATORS IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA TREATED WITH TARGETED THERAPY

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) I1 Apr 2016MP03-08 COMPREHENSIVE ANALYSIS AND VALIDATION OF CONTEMPORARY SURVIVAL PROGNOSTICATORS IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA TREATED WITH TARGETED THERAPY Kyo Chul Koo, Kwang Suk Lee, Kang Su Cho, Koon Ho Rha, Sung Joon Hong, Byung Ha Chung, and Dong Hyeon Lee Kyo Chul KooKyo Chul Koo More articles by this author , Kwang Suk LeeKwang Suk Lee More articles by this author , Kang Su ChoKang Su Cho More articles by this author , Koon Ho RhaKoon Ho Rha More articles by this author , Sung Joon HongSung Joon Hong More articles by this author , Byung Ha ChungByung Ha Chung More articles by this author , and Dong Hyeon LeeDong Hyeon Lee More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1901AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In line with the era of targeted-therapy (TT), an increasing number of prognosticators are becoming available for patients with metastatic renal cell carcinoma (mRCC). Here, potential prognosticators of cancer-specific survival (CSS) were identified based on the contemporary literature, and were comprehensively validated in an independent cohort of patients treated for mRCC. METHODS Data were collected from 478 patients treated with TT for mRCC between January 1999 and July 2013 at a single institution. The analysis included 24 clinicopathological covariates that included both traditional and contemporary prognosticators: age, sex, body mass index, Karnofsky performance status (KPS), Charlson Comorbidity Index, anemia, neutrophilia, neutrophil-to-lymphocyte ratio (NLR), thrombocytosis, hypercalcemia, T and N stages, tumor size, grade, subtype, sarcomatoid feature, tumor thrombus, number and location of metastasis, lymph node metastasis (supradiaphragmatic vs. subdiaphragmatic), cytoreductive nephrectomy, time from diagnosis to TT, number of TT lines, and tumor response following TT. Multivariate Cox-regression models were used to quantify the effect of covariates on CSS. RESULTS Median survival from the initial diagnosis of metastasis was 24.5 (IQR 11.5-55.7) months. There were 303 (63.4%) cancer-specific deaths, yielding a 2-year CSS rate of 62.5%. Low KPS, hypercalcemia, NLR, the number of metastatic sites (≥2), and the presence of brain metastases were independent adverse prognosticators of CSS. Patients with at least one adverse prognosticator demonstrated lower 2-year CSS rates compared to those with no prognosticators (53.9% vs. 70.6%; log-rank p<0.001). CONCLUSIONS Together with traditional prognosticators such as KPS and hypercalcemia, the number and location of metastases and NLR were independent predictors of CSS in patients with mRCC treated with TT. Our findings could be useful for guiding clinical decision-making including stratification of patients for TT and inclusion in clinical trials. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e21-e22 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Kyo Chul Koo More articles by this author Kwang Suk Lee More articles by this author Kang Su Cho More articles by this author Koon Ho Rha More articles by this author Sung Joon Hong More articles by this author Byung Ha Chung More articles by this author Dong Hyeon Lee More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Comprehensive analysis and validation of contemporary survival prognosticators in Korean patients with metastatic renal cell carcinoma treated with targeted therapy: prognostic impact of pretreatment neutrophil-to-lymphocyte ratio.

In line with the era of targeted therapy (TT), an increasing number of prognosticators are becoming available for patients with metastatic renal cell carcinoma (mRCC). Here, potential prognosticators of cancer-specific survival (CSS) were identified based on the contemporary literature and were comprehensively validated in an independent cohort of patients treated for mRCC. Data were collected from 478 patients treated with TT for mRCC between January 1999 and July 2013 at a single institution. The analysis included 25 clinicopathological covariates that included both traditional and contemporary prognosticators. Multivariate Cox regression models were used to quantify the effect of covariates on CSS. Median survival from the initial diagnosis of metastasis was 24.5 (IQR, 11.5-55.7) months. There were 303 (63.4%) cancer-specific deaths, yielding a 2-year CSS rate of 62.5%. Low Karnofsky performance status (KPS), hypercalcemia, neutrophil-to-lymphocyte ratio (NLR), the number of metastatic sites (≥2), and the presence of brain metastases were independent adverse prognosticators of CSS. The C-index of the model was 0.78. Patients with at least one adverse prognosticator demonstrated lower 2-year CSS rates compared to those with no prognosticators (53.9 vs. 70.6%; log rank p<0.001). Together with traditional prognosticators such as KPS, hypercalcemia, and the number and location of metastases, the NLR was an independent predictor of CSS in patients with mRCC treated with TT. Our findings could be useful for guiding clinical decision making including stratification of patients for TT and inclusion in clinical trials.

Depression and anxiety among family caregivers of patients with advanced cancer.

224 Background: Despite the important role family caregivers (CGs) play in the care of patients with cancer, little is known about their psychological distress. We sought to describe rates and correlates of depression and anxiety in CGs of patients with advanced cancer to determine those at greatest risk for psychological distress. Methods: As part of an ongoing trial of early palliative care, we are assessing baseline depression and anxiety in patients within 8 weeks of advanced lung or gastrointestinal cancer diagnosis and their CGs. We are administering the Hospital Anxiety and Depression Scale (HADS), with subscale scores &gt;7 denoting clinically significant depression or anxiety. We are assessing patient coping styles with the Brief COPE. We used multiple logistic regression with purposeful selection of covariates to identify correlates of CG depression and anxiety. Results: Of 240 CGs (mean age=57 years), 156 (65%) were spouses/partners, 167 (70%) were female, and 131 (55%) were working. 37 (15%) and 102 (43%) CGs reported significant depression and anxiety, respectively. CG age, gender and employment status, as well as patients’ anxiety and lack of acceptance coping were associated with higher rates of CG depression. CG age, gender, marital status and education level, as well as patients’ anxiety and presence of brain metastases were associated with higher rates of CG anxiety. Conclusions: Younger, female CGs were at greatest risk of both depression and anxiety. Thus, this CG population should be monitored closely and referred for cancer center support services for distress management. We also found that patients’ anxiety was associated with higher rates of both CG depression and anxiety, underscoring the importance of interventions that address both patient and CG psychological distress. Clinical trial information: NCT01401907. [Table: see text]

Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients.

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0–1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

2586 Pattern of presentation of brain metastases (BM) in metastatic renal cell cancer (mRCC) patients (pts) treated with targeted therapies (TT): Implications for screening practice

2586 Pattern of presentation of brain metastases (BM) in metastatic renal cell cancer (mRCC) patients (pts) treated with targeted therapies (TT): Implications for screening practice

Abstract 4329: Expression of serpin B2, neuroserpin and L1CAM in association with metastasis and survival in non-small cell lung cancer

Abstract Background: Lung cancer is a leading cause of cancer related deaths worldwide, and finding new prognostic and predictive biomarkers are of utmost importance. Previous studies have shown that different serpins and adhesion molecules have an impact on disease progression and development of metastasis, especially to the brain. Here, we examined whether expression of the anti-plasminogen activators Serpin B2 and Neuroserpin, and the adhesion molecule L1CAM was associated with patient prognosis, brain metastasis or other clinicopathologic characteristics, in non-small cell lung cancer (NSCLC). Study design: The material consists of surgical specimens from 100 NSCLC patients treated during 1993-1999 at Haukeland University Hospital, Bergen, Norway. Sections from tumor blocks were stained with antibodies to Serpin B2, Neuroserpin, and L1CAM. Results: There were 66 men and 34 women, with a mean age at diagnosis of 65.7 (41 adenocarcinomas, 38 squamous cell carcinomas, and 21 carcinomas of other types). Observation time ranged from 0 to 254 months (mean 74 months). 12 patients were fully recovered, 46 died of lung cancer, and 34 died from other causes. 11 of 89 patients developed brain metastasis. Low expression of Serpin B2 was associated with reduced overall survival (p&amp;lt;0.05) in adenocarcinomas, and with a trend for all types combined (p = 0.10), whereas there was no significant difference in survival related to expression of Neuroserpin or L1CAM. Expression of Neuroserpin was associated with adrenal metastasis (OR 13.3 (95%CI 1.5-119.7), p&amp;lt;0.05), and there were trends for associations between expression of Serpin B2 and metastases to skin and bone (p = 0.072 and p = 0.068, respectively). There were no significant associations between these markers and presence of brain metastasis. Conclusions: Low expression of Serpin B2 in lung adenocarcinoma was associated with reduced overall survival in our cohort. In contrast to previous findings by others, we did not find a relationship between L1CAM expression and overall survival or metastasis. Neither was there any association between expression of Neuroserpin and survival, although we found an increase in adrenal metastasis in this group. Low expression of Serpin B2 could be a biomarker for prognosis in lung adenocarcinomas and should be studied in other cohorts. Citation Format: Maria Ramnefjell, Lars Helgeland, Lars A. Akslen. Expression of serpin B2, neuroserpin and L1CAM in association with metastasis and survival in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4329. doi:10.1158/1538-7445.AM2015-4329

The Effect of Receiving Treatment Within a Clinical Trial Setting on Survival and Quality of Care Perception in Advanced Stage Non–Small Cell Lung Cancer

Treatment outcomes of advanced stage (IIIB and IV) non-small cell lung cancer (NSCLC) are poor. In this study, we explore the survival outcomes and the perception of the quality of care delivered in stage IIIB and IV NSCLC patients treated within versus outside a clinical trial. Data were obtained from the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS). Baseline characteristics according to clinical trial participation were determined. The association between clinical trial enrollment and survival was assessed using a Cox proportional hazard model after adjusting for age, income, primary data collection and research site, comorbidities, self-reported performance status, presence of brain metastasis, stage IIIB versus IV, and cancer histology. Of 815 stage IIIB and IV NSCLC patients, 56 (7%) were enrolled in clinical trials. Median survival for the patients treated within versus outside a clinical trial was 20.5 versus 16.7 months, respectively (P=0.21). Using a multivariate survival model, clinical trial enrollment did not correlate with longer survival (P=0.81). Comparing patients according to clinical trial enrollment, patients treated within a clinical trial setting perceived a better overall quality of care (P<0.01). Management of stage IIIB and IV NSCLC patients within a clinical trial setting conveyed a perception of superior care that did not translate into survival benefit. These findings suggest that providing cancer care within a clinical trial should not imply a survival benefit when counseling stage IIIB and IV NSCLC patients about entering clinical trials.

Impact of Smoking and Brain Metastasis on Outcomes of Advanced EGFR Mutation Lung Adenocarcinoma Patients Treated with First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

ObjectivesThis purpose of this study was to examine clinical-pathologic factors – particularly smoking and brain metastases – in EGFR mutation positive (M+) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI.MethodsA retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M+ ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival.Results444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M+. Amongst never-smokers (n=468), EGFR M+ were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson’s chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival.ConclusionsThe high prevalence of EGFR M+ in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.

Anti-angiogenic therapy in advanced non-small cell lung carcinoma (NSCLC): is there a role in subsequent lines of therapy?

Early in 2014, Reck and colleagues published the results of the LUME Lung-1 trial in Lancet Oncology (1). This trial evaluated the addition of nintedanib, an oral triple angiokinase inhibitor or placebo, to standard second-line chemotherapy with docetaxel. The trial, conducted largely in European countries, randomized 1,314 patients to docetaxel plus nintedanib 200 mg twice daily, or docetaxel plus placebo. Treatment continued until disease progression, or unacceptable toxicity. Eligible patients had stage IIIB/IV or recurrent non-small cell lung carcinoma (NSCLC) that had progressed after first-line chemotherapy. Patients with contraindications to the use of VEGF-R directed therapy (untreated brain metastases, underlying major bleeding or thrombotic disorders, cavitatory lesions, lesions invading major blood vessels and a history of hemoptysis) were excluded. Prior therapy with bevacizumab was allowed, although fewer than 5% of patients in both arms had previously received bevacizumab. Stratification was based on Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1), prior bevacizumab therapy (yes vs. no), squamous versus non squamous histology, and the presence of brain metastases (yes vs. no). The primary outcome was progression free survival (PFS).

Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers.

Brain metastases (BM) are common in non-small-cell lung cancer (NSCLC). However, the baseline incidence and evolution of BM over time in oncogene-driven NSCLCs are seldom reported. In this study, we evaluated the frequency of BM in patients with epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC. The presence of BM, clinicopathologic data, and tumor genotype were retrospectively compiled and analyzed from a cohort of 381 patients. We identified 86 EGFR-mutated (90.7% with metastatic disease; 85.9% received an EGFR inhibitor) and 23 ALK-rearranged (91.3% with metastatic disease; 85.7% received an ALK inhibitor) NSCLCs. BM were present in 24.4% of EGFR-mutated and 23.8% of ALK-rearranged NSCLCs at the time of diagnosis of advanced disease. This study did not demonstrate a difference in the cumulative incidence of BM over time between the two cohorts (EGFR/ALK cohort competing risk regression [CRR] coefficient of 0.78 [95% CI 0.44-1.39], p=0.41). In still living patients with advanced EGFR-mutated NSCLC, 34.2% had BM at 1 year, 38.4% at 2 years, 46.7% at 3 years, 48.7% at 4 years, and 52.9% at 5 years. In still living patients with advanced ALK-rearranged NSCLC, 23.8% had BM at 1 year, 45.5% at 2 years, and 58.4% at 3 years. BM are frequent in advanced EGFR-mutated or ALK-rearranged NSCLCs, with an estimated >45% of patients with CNS involvement by three years of survival with the use of targeted therapies. These data point toward the CNS as an important unmet clinical need in the evolving schema for personalized care in NSCLC.

Management of high risk gestational trophoblastic disease with brain metastases - A single institution experience from 1996 to 2010

Objective: Gestational trophoblastic disease (GTD) is a peculiar disease in females of reproductive age group because of their natural history, management, high potential for bleeding and excellent response to chemotherapy. Although the incidence of brain metastases is only 10%, propensity for uncontrollable hemorrhage in brain parenchyma makes this situation, a medical emergency. We discuss case series of 7 patients with high risk GTD with brain metastases and their management. Study Design: A retrospective analysis of 15 years from January 1996 to December 2010 was done to study all cases of GTD treated in this institution. Patients who presented with brain metastases on initial diagnosis (early group) and who had metachronous disease (late group) during the course of treatment or follow-up were summarized in this study. Materials and Methods: Of 1208 cases of hydatidiform mole treated in this institution, 325 cases had low risk (WHO score 6 or less), and 38 patients had metastatic disease (score 7 and more). Seven cases were diagnosed to have a high risk GTD with brain metastases, 5 (71.43%) presented initially and 2 (28.57%) developed late brain metastases. Results: In our analysis, patients who had brain metastases on presentation had better survival (median = 52 months, range = 18-61) compared with patients who developed brain disease later in the course (median = 5.5 months, range = 3-8). Conclusion: Gestational trophoblastic disease with early brain metastases presentation showed better response and survival compared with late presentation group.

Outcome of patients with an initial presentation of brain metastases.

133 Background: Many studies have looked at the survival of patients with brain metastases but few studies have determined if the survival of patients initally presenting with brain metastases is the same as patients who subsequently develop brain metastases. Methods: Patients with no known history or a malignancy who presented to the hospital with brain metastases were retrospectively revieweed for survival. The survival data were collected from the hospital's tumor registryand the Social Security Index. The years 2010-2011 were studied as of 5/31/2013. Results: Ninety-four patients met the inclusion criteria in 2010 and eight-two patients in 2011. Sixty five percent of the patients in 2010 were male and fifty-five percent were male in 2011. The median age was approximately 60. In 2010 53% of the patients had lung cancer and 12% had breast cancer and in 2011 45% had lung cancer and 13% had breast cancer. zThus the median survival is equivalent to the median survival of the lung cancer patients, which was 71 days in 2010 and 37 days in 2011. the median survival of the breast cancer patients were 153 days in 2010 and 35 days in 2011. Sixty three percent of the patients received radiation therapy as some part of their treatment and eighteen percent received no treatment. The median survival time of patients receiving radiation therapy only as treatment was 84 days and the patients with no treatment had a survival of 34 days. Conclusions: The survival of patients presenting with brain metastases falls within the range expected from previous studies of patients with brain metastases. The survival of patients presenting with lung cancer was much poorer than patients with breast cancer. Patients for no treatment appear to be appropriately selected, with a median surival of approximately one month.

Controversies in the management of advanced melanoma: "gray" areas amid the "black and blue".

To examine the current controversies and discuss consensus recommendations regarding treatment sequencing and the role of BRAF inhibitor at disease progression. An English-language literature search of MEDLINE/PubMed (1966-May 2014), using the keywords advanced melanoma, ipilimumab, cytotoxic T-lymphocyte antigen 4, dabrafenib, vemurafenib, BRAF inhibitor, trametinib, MEK inhibitor, and treatment sequencing was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries. All relevant published articles and abstracts on ipilimumab, vemurafenib, dabrafenib, and trametinib were reviewed. Clinical trial registries and meeting abstracts were used for ongoing studies. The availability of new agents has made therapy selection more complex. Immunotherapy supporters reason that immunotherapy offers the best chance for long-term benefit and does not compromise the antitumor activity of subsequent BRAF inhibitors. Targeted therapy advocates rely on the high probability and rapid onset of response to BRAF inhibitors. Currently, there is insufficient evidence regarding the role of BRAF inhibitor at disease progression. Therapy should be individualized based on patient- and disease-specific factors. Immunotherapy represents the best option for durable remission; however, targeted therapy is more appropriate for patients who are symptomatic or have rapidly growing tumors. The novel therapies have also demonstrated meaningful intracranial activity; thus, the presence of brain metastases should be taken into consideration in selecting therapy. Limited data exist about the continuation of BRAF inhibitors after therapeutic failure. Active research is ongoing to define the best option for patients with BRAF inhibitor refractory disease.

Immuno-Expression of Endoglin and Smooth Muscle Actin in the Vessels of Brain Metastases. Is There a Rational for Anti-Angiogenic Therapy?

Despite ongoing clinical trials, the efficacy of anti-angiogenic drugs for the treatment of brain metastases (BM) is still questionable. The lower response rate to anti-angiogenic therapy in the presence of BM than in metastatic disease involving other sites suggests that BM may be insensitive to these drugs, although the biological reasons underlining this phenomenon are still to be clarified. With the aim of assessing whether the targets of anti-angiogenic therapies are actually present in BM, in the present study, we analyzed the microvessel density (MVD), a measure of neo-angiogenesis, and the vascular phenotype (mature vs. immature) in the tumor tissue of a series of BM derived from different primary tumors. By using immunohistochemistry against endoglin, a specific marker for newly formed vessels, we found that neo-angiogenesis widely varies in BM depending on the site of the primary tumor, as well as on its histotype. According to our results, BM from lung cancer displayed the highest MVD counts, while those from renal carcinoma had the lowest. Then, among BM from lung cancer, those from large cell and adenocarcinoma histotypes had significantly higher MVD counts than those originating from squamous cell carcinoma (p = 0.0043; p = 0.0063). Of note, MVD counts were inversely correlated with the maturation index of the endoglin-stained vessels, reflected by the coverage of smooth muscle actin (SMA) positive pericytes (r = −0.693; p < 0.0001). Accordingly, all the endoglin-positive vessels in BM from pulmonary squamous cell carcinoma and renal carcinoma, displayed a mature phenotype, while vessels with an immature phenotype were found in highly vascularized BM from pulmonary large cell and adenocarcinoma. The low MVD and mature phenotype observed in BM from some primary tumors may account for their low sensitivity to anti-angiogenic therapies. Although our findings need to be validated in correlative studies with a clinical response, this should be taken into account in therapeutic protocols in order to avoid the adverse effects of useless therapies.

Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial

The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m(2) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8-11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9-3·9] vs 2·7 months [2·6-2·8]; hazard ratio [HR] 0·79 [95% CI 0·68-0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8-36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5-12·6] vs 7·9 months [6·7-9·1]; HR 0·75 [95% CI 0·60-0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6-15·1] vs 10·3 months [95% CI 8·6-12·2]; HR 0·83 [95% CI 0·70-0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8-11·2] vs 9·1 months [8·4-10·4]; HR 0·94, 95% CI 0·83-1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. Boehringer Ingelheim.

Outcomes of palliative weekly low-dose gemcitabine-Cisplatin chemotherapy in anthracycline- and taxane- pretreated metastatic breast cancer patients.

PurposeThe combination of gemcitabine and cisplatin (GP) has been shown to be safe and efficacious for patients with metastatic breast cancer (MBC), pretreated with anthracyclines and taxanes. We assessed the efficacy and safety of weekly low-dose GP in patients with MBC.MethodsWe collected clinicopathological data from MBC patients who had been treated with gemcitabine, 800 mg/m2 plus cisplatin, 30 mg/m2 intravenously, on days 1 and 8 every 3 weeks, between January 2001 and November 2011 in Korea.ResultsThe analysis included 294 patients previously treated anthracycline-xand taxane-based chemotherapies prior to GP (median age, 48 years [range, 28-78 years]; median follow-up duration, 63.9 months). Seventeen patients (5.8%) discontinued GP because of toxicities. The median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI], 3.394.4 months) and the median overall survival (OS) was 27.7 months (95% CI, 17.6-37.8 months) months. Statistically significant factors for PFS were performance status (Eastern Cooperative Oncology Group, ≥2 vs. <2; hazard ratio [HR], 1.37; 95% CI, 1.02-1.85; p=0.037), distant disease-free interval (DDFI; ≤2 years vs. >2 years; HR, 1.66; 95% CI, 1.28-1.95, p<0.001), time interval from the diagnosis of metastasis to GP therapy (≤1 year vs. >1 year; HR, 1.48; 95% CI, 1.13-1.95, p<0.001), and presence of brain metastasis (HR, 1.47; 95% CI, 1.03-2.10; p=0.031). Similarly, DDFI (≤2 years vs. >2 years; HR, 2.07; 95% CI, 1.36-3.14; p<0.001) and the presence of brain metastasis (HR, 2.14; 95% CI, 1.27-3.61; p=0.004) were important factors for OS after GP treatment.ConclusionWeekly low-dose GP chemotherapy appears safe and effective for heavily pretreated MBC patients.

MRI Findings of Brain Metastases in Lung Cancers

Brain metastasis is a serious clinical problem in patients with lung cancers and a particular factor affecting the mortality and morbidity. The presence of brain metastasis and the number of the metastatic focusi are important for the treatment decision. In this study we aimed to analyze the brain metastases due to lung cancers retrospectively. The study involved 103 patients who had brain metastases. The patients were evaluated in terms of localizations of the brain metastases, histopathologic types, lesion characteristics and solidarity or multiplicity. In all of the cases, the most frequent metastases were to frontal lobe (38,5%). In SCLC and NSCLC, frontal lobe was the most frequent metastatic localization. In all the metastatic focusi, 46.6% of multiple and 53.4% of solid brain metastases were present. The multiple metastasis rate detected in SCLC’s was 82.3% and was the greatest in all the cases. The squamous cell cancers had 67.5% solid metastasis and this rate was the highest among all the types. Also, our study showed that brain metastasis of lung cancer cases had solid characteristics of 59.3%, the 38.3% included cystic component and 6.1% had hemorrhagic characteristics. In epidermoid carcinomas, cystic metastases were the most to be detected and the rate was 69.7%. In the hemorrhagic metastatic types, adenocarcinomas had the highest rate with 10.7%. In conclusion, we suppose that in lung cancers, the properties of the brain metastases will offer a positive prediction for the method prior to the treatment. However, since the metastases from the epidermoid lung cancers are frequently located in frontal lobe and mostly as single lesions, we predict that these would benefit more from the treatment.

Serum S100B, Lactate Dehydrogenase and Brain Metastasis Are Prognostic Factors in Patients with Distant Melanoma Metastasis and Systemic Therapy

BackgroundPrognostic factors of melanoma with distant metastasis and systemic treatment are only poorly established. This study aimed to analyse the impact of S100B, lactate dehydrogenase (LDH) and the type of treatment on survival in advanced patients receiving systemic treatment.Patients and MethodsWe analysed overall survival of 499 patients from the university department of dermatology in Tuebingen, Germany, with unresectable melanoma at the time point of initiation of first-line systemic therapy. Only patients who started treatment between the years 2000 and 2010 were included. Disease-specific survival was calculated by bivariate Kaplan Meier survival probabilities and multivariate Cox hazard regression analysis.ResultsIn univariate analysis LDH, S100B, the site of distant metastasis (soft tissue vs. lung vs. other visceral), the presence of brain metastases and the type of treatment (monochemotherapy, polychemotherapy, immunotherapy or biochemotherapy) were associated with overall survival (all p<0.001). In multivariate analysis LDH (Hazard ratio [HR] 1.6 [1.3–2.1]; p<0.001), S100B (HR 1.6 [1.2–2.1]; p<0.001) and the presence of brain metastases (HR 1.5 [1.1–1.9]; p = 0.009), but not the type of treatment had significant independent impact. Among those factors normal S100B was the best indicator of long-term survival, which was 12.3% after 5 years for this subgroup.ConclusionSerum S100B is a prognostic marker predicting survival at the time of initiation of first-line treatment in unresectable melanoma patients. Compared to the other independent factors LDH and the presence of brain metastases it is most appropriate to predict long-term survival and requires further prospective investigation in patients treated with new and more potent drugs in metastatic melanoma.

The frequency of falls in patients with advanced cancer followed in an outpatient palliative care center.

225 Background: Falls are a concern in patients who are frail, have advance age or severe underlying medical condition as a significant cause of morbidity and reduced quality of life. It has been reported to occur in up to 50% of palliative care patients in different settings. Our aim was to determine the frequency of falls and identify its predictors and correlates in patients with advanced cancer. Methods: We reviewed 1,984 consecutive patients with advanced cancer seen in the outpatient supportive care center and determined the frequency of patient reported falls within the last month prior to the visit. Baseline patient characteristics, symptom severity scores in the Edmonton Symptom Assessment Scale (ESAS), medication use, functional status, and use of assistive devices were used to identify factors that are predictive of falls using backwards stepwise logistic regression. Results: 1,041 (52%) were female, 1,377 (69%) were non-Hispanic-white, 343 (17%) had peripheral neuropathy, 237 (12%) were on psychotropic medications, and 1,140 (58%) were on opioids. There were 211 (11%) patient reported falls. Presence of brain metastasis, use of assistive device, ECOG, ESAS depression, and weight prior to visit were significantly associated with patient reported falls in the multivariate model. Conclusions: One tenth of patients seen in the outpatient supportive care clinic reported falls. Our findings showing that falls to be associated with brain metastasis, assistive device, functional status, ESAS depression and weight are useful in stratifying high risk patients. They also show that certain medications deemed as risk factors in other populations were not associated with falls. [Table: see text]