Growth rate of newly developed metastatic brain tumors after thoracotomy in patients with non-small cell lung cancer

Among 1372 lung cancer patients without brain metastasis that underwent resection of lung cancer at our center from 2001 to 2007, brain metastases developed in 72 patients (5.2%) during their hospital course. We hypothesized that there were micro-metastases in the brain at the time of lung surgery in these patients, even though there were no detectable brain metastases on the MRI. The purpose of this study was to evaluate the growth rates of metastatic brain tumors in this unique subset of patients, and to compare the findings with our previous study that calculated the growth rate of brain metastases during chemotherapy. Among 72 patients, 23 with cystic or hemorrhagic metastases were excluded. Seventy-six metastatic brain tumors in 49 patients were reviewed. Twenty-five patients underwent adjuvant or neoadjuvant chemotherapy; however, for the rest of the patients, chemotherapy was not added after lung cancer surgery. The tumor volume was determined using V-works software (v. 4.0) (Cybermed, Seoul, Korea) and T1 gadolinium enhanced MR images. The overall median tumor growth rate was 11.7 mm³/day (interquartile range, 4.9-26.8). There were no statistically significant differences in the tumor growth among the lung cancer stages and the growth rate was similar regardless of the use of chemotherapy. The growth rate reported in this study shows consistency with that of our previous report (12.1 mm³/day). These findings may help optimize patient management during follow up.     

Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer

BACKGROUND:

The discovery of distinct subsets of nonsmall cell lung cancer (NSCLC) characterized by activation of driver oncogenes has greatly affected personalized therapy. It is hypothesized that the dominant oncogene in NSCLC would be associated with distinct patterns of metastatic spread in NSCLC at the time of diagnosis.

METHODS:

A total of 209 consecutive patients with stage IV nonsquamous NSCLC with an EGFR (epidermal growth factor receptor) mutation (N = 39), KRAS (v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog) mutation (N = 49), ALK (anaplastic lymphoma receptor tyrosine kinase) gene rearrangement (N = 41), or wild‐type for all 3 (triple negative, N = 80) were included. The percentage of patients with metastatic disease at a given site was compared between each molecular cohort (EGFR, KRAS, or ALK) and the triple negative cohort.

RESULTS:

ALK gene rearrangement was significantly associated with pericardial disease (odds ratio [OR] = 4.61; 95% confidence interval [CI] = 1.30, 16.37; P = .02) and pleural disease (OR = 4.80; 95% CI = 2.10, 10.97; P < .001). Patients with ALK gene rearrangements (OR = 5.50; 95% CI = 1.76, 17.18; P = .003) and patients with EGFR mutations (OR = 5.17; 95% CI = 1.63, 16.43; P = .006) were predisposed to liver metastasis compared to the triple negative cohort. No molecular cohort had a predisposition to pulmonary nodules, or adrenal, bone, or brain metastasis compared to the triple negative cohort. The mean number of metastatic disease sites in patients within the ALK rearranged cohort was significantly greater than that of the triple negative cohort (mean = 3.6 sites vs 2.5 sites, P < .0001).

CONCLUSIONS:

The results support the hypothesis that the dominant molecular oncogenes in NSCLC are associated with different biological behaviors manifesting as distinct patterns of metastatic spread at the time of diagnosis. Cancer 2012. © 2012 American Cancer Society.     

Chemoradiotherapy of nonsmall cell lung cancer

The efficacy of radiotherapy in locally advanced unresectable non-small cell lung cancer is low. This method does not provide effective eradication of bulky disease in the thorax, neither does it prevent uncontrolled systemic disease. The addition of chemotherapy to radiation results in increased cure rate by both improving tumor control in the thorax and by eliminating or delaying the emergence of metastatic disease. The two most frequently tested strategies of combining chemotherapy and radiation include primary chemotherapy followed by radiation and concurrent application of both methods. This review provides the rationale for this strategy and presents the results of major Phase III studies. Discussed are advantages of chemoradiation, its limitations in clinical practice and prospects for the future.     

非小细胞肺癌原发灶与脑转移灶EGFR基因突变状况的一致性研究

目的 探讨非小细胞肺癌（NSCLC）原发灶与脑转移灶的表皮生长因子受体（EGFR）基因突变状况,分析两者之间是否存在一致性。方法 收集2003年1月至2011年12月31例NSCLC脑转移患者的肺原发灶和脑转移灶石蜡包埋组织标本,应用DNA直接测序法进行EGFR突变分析,如发现两者突变不一致则进一步采用增殖阻碍突变系统 （ARMS）验证。结果 31例NSCLC肺原发灶中,8例存在19外显子E746-A750缺失突变、4例为21外显子L858R点突变;在31例脑转移灶样本中,8例为19外显子E746-A750缺失突变,3例存在21外显子L858R点突变,EGFR突变类型在脑转移灶和肺原发灶的分布差异无统计学意义 （P=0.793）。共有16.1％ （5／31）的肺原发灶和脑转移灶EGFR突变状况不一致,其中男性4例,女性1例;3例腺癌 （2例脑转移灶19外显子缺失突变而肺原发灶阴性突变,1例肺原发灶21外显子点突变而脑转移灶阴性突变）,1例鳞癌和1例非典型类癌 （均为脑转移灶阴性突变而肺原发灶19外显子缺失突变）。结论 NSCLC原发病灶及脑转移灶EGFR基因突变存在不一致性。     

Positron emission tomography in nonsmall cell lung cancer

PURPOSE OF REVIEW: Positron emission tomography (PET) has become a major adjunct to structural imaging for nonsmall cell lung cancer. Established indications are the differential diagnosis of lung nodules, as well as mediastinal lymph node and extrathoracic staging. RECENT FINDINGS: More details for small or faint pulmonary nodules became available--information of interest in the era of lung cancer screening trials, in which PET might help to reduce unwanted invasive procedures for benign findings. The strength of PET in mediastinal staging (its high negative predictive value) was confirmed in a randomized study, in which PET reduced the number of invasive procedures without loss of accuracy in staging. Isolated positive lesions that are decisive for radical compared with palliative treatment should be confirmed by other tests, as they may be benign or due to second primary cancer. PET with integrated computed tomography (CT) may guide modern radiotherapy, by improving radiation fields. Integrated PET-CT is a promising tool in the indication for surgery in stage IIIA-N2 patients after induction treatment. Predictive values for lymph node downstaging become in acceptable ranges and PET response in the primary tumor could be clearly linked to pathologic response and survival. SUMMARY: In recent years, PET has seen further refinements in established indications and definition of new indications.     

Venous thromboembolism and nonsmall cell lung cancer

BACKGROUND:

Advanced nonsmall cell lung cancer (NSCLC) is associated with venous thromboembolism (VTE). However, to the authors' knowledge, the incidence of VTE in early NSCLC, predictors of VTE, and the prognostic significance of VTE in NSCLC have not been explored.

METHODS:

Individual patient data from 3 National Cancer Institute of Canada Clinical Trials Group trials were analyzed (n = 1987 patients). Clinical Trial BR.10 was a randomized study of postoperative vinorelbine and cisplatin versus observation in patients with stage IB/II NSCLC (grading determined according to the TNM staging system). Clinical Trial BR.18 was a randomized study of paclitaxel and carboplatin with or without the metalloproteinase inhibitor BMS‐275291 in patients with advanced NSCLC. BR.21 was a randomized study of erlotinib versus placebo in patients with previously treated NSCLC. The relations between VTE, treatment, concomitant medications, and patient characteristics were explored in univariate and multivariate analyses. Survival analysis was completed using Cox regression.

RESULTS:

The incidence of VTE ranged from 0% in patients with early stage NSCLC on the observation arm of BR.10 to 7.9% in patients with advanced NSCLC who received chemotherapy (BR.18). Patients with early stage NSCLC who received chemotherapy (BR.10) and patients with previously treated NSCLC who received erlotinib or placebo (BR.21) had a VTE incidence of ～3%. Factors that were found to be predictive of VTE included previous VTE (BR.18; P = .001) and obesity (BR.10; P = .03). In patients with advanced NSCLC, VTE was associated with shorter survival (BR.18: hazard ratio [HR], 1.61; 95% confidence interval [95% CI], 1.26‐2.07 [P = .0002]; BR.21: HR, 2.18; 95% CI, 1.57‐3.04 [P < .0001]).

CONCLUSIONS:

In patients with both early stage and advanced stage NSCLC, VTE occurred more frequently in patients who received chemotherapy (but not erlotinib or BMS‐275291). In patients with advanced stage NSCLC, VTE was associated with obesity and a history of VTE. VTE was found to be prognostic in patients with advanced stage NSCLC. Cancer 2009. © 2009 American Cancer Society.     

全脑放疗联合化疗在非小细胞肺癌脑转移中的应用

目的探讨全脑放疗联合化疗在非小细胞肺癌脑转移中的应用。方法选取2011年1月至2014年12月间临清市人民医院收治的120例非小细胞肺癌脑转移患者作为研究对象,按照入院顺序,将2011年1月至2012年12月间入院的60例患者分为对照组,将2013年1月至2014年12月间入院的60例患者分为观察组。观察组患者用全脑放疗联合替莫唑胺治疗,对照组患者用全脑放疗。治疗后3个月比较两组患者的近期疗效,统计两组患者的无进展生存期(PFS)和1年生存率,并比较两组患者的不良反应发生情况。结果观察组患者的客观缓解率为91.7%,对照组为51.7%,差异有统计学意义(P<0.05),两组患者PFS的差异无统计学意义(P>0.05),观察组患者的1年生存率明显高于对照组,差异有统计学意义(P<0.05),两组患者不良反应发生情况的差异无统计学意义(P>0.05)。结论全脑放疗联合替莫唑胺治疗非小细胞肺癌脑转移具有疗效好,生存率高且不良反应未增加等优势,适合临床推广应用。     

Number of metastatic sites is a strong predictor of survival in patients with nonsmall cell lung cancer with or without brain metastases

BACKGROUND:

The staging system for non–small cell lung cancer (NSCLC) does not consider tumor burden or number of metastatic sites, although oligometastases are more favorable.

METHODS:

Using log‐rank testing, the authors analyzed overall survival (OS) in 1284 patients newly presenting with metastatic NSCLC by number of metastatic organ sites and the presence of brain metastases.

RESULTS:

OS for patients without brain metastases was found to be correlated with the number of metastatic sites (P = .0009). Brain metastases conferred an inferior OS (median of 7 months vs 9 months; 95% confidence interval, 7‐8 months vs 8‐10 months [P = .00,002]). To evaluate the influence of tumor burden on OS, the authors considered subsets of patients in whom the brain (n = 135) or lung (n = 137) was the solitary metastatic organ site. In patients with brain metastases, OS was found to be correlated inversely with the volume of all metastases or the largest lesion (hazards ratio, 1.04 or 1.03, respectively; P = .01). For patients with lung metastases, OS was better for those with a maximum tumor size below the median of 40 mm (P = .0004).

CONCLUSIONS:

Staging of NSCLC and clinical trial patient stratification should include quantitation of tumor burden. The prognostic impact of brain metastases is small and partly dependent on tumor volume, which indicates the need for aggressive therapy for patients with NSCLC brain metastasis and their inclusion in clinical trials. Cancer 2009. © 2009 American Cancer Society.     

EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer

A small subset of patients with nonsmall cell lung cancer (NSCLC) harbors mutations in the epidermal growth factor receptor (EGFR) that predict unique sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The characteristics and behavior of brain metastases (BMs) in these patients have not been well described. The longitudinal records of all NSCLC patients who underwent EGFR mutation screening at our center from August 2004 to November 2008 were reviewed for eligibility, and 93 patients were identified who developed BM during the course of their disease. Survival was estimated using the Kaplan–Meier method and the log-rank test. Multivariable predictors were assessed via the Cox proportional hazards model. Among the 93 patients with BM, 41 (44%) had mutations in EGFR, including 13 exon 19 deletions and 12 L858R mutations. Eighty-three percent of patients with BM were treated initially with whole brain radiation, either alone (53%) or in combination with craniotomy for neurosurgical resection (22%) or stereotactic radiosurgery (8%). Median survival from the time of BM was 11.7 months and was longer for patients with an EGFR mutation (14.5 vs 7.6 months, P = .09). On multivariable analysis, EGFR mutation (HR: 0.50, 95% CI: 0.30–0.82), age (HR: 1.03, 95% CI: 1.00–1.05), and active extracranial disease (HR: 3.30, 95% CI: 1.70–6.41) were independently associated with survival. In NSCLC patients with BM, EGFR mutation status is associated with improved survival, independent of age, functional status, extracranial disease status, and number of BMs.     

肺癌脑转移细胞的筛选及实验动物模型的建立

目的：通过反复裸鼠体内肺癌细胞接种,筛选出特异性脑转移肺癌细胞株,并建立可稳定产生脑转移的肺癌实验动物模型.方法：应用人肺癌细胞株PC-14尾静脉注射接种裸鼠,5周后处死裸鼠,取出脑转移肿瘤组织,行原代培养后再次接种裸鼠,反复几个循环,观察脑转移形成情况.结果：经过4个循环后,筛选出的PC-14/B肺癌细胞尾静脉接种可在裸鼠产生特异脑转移,可应用于建立稳定转移的肺癌脑转移实验动物模型.结论：应用肺癌细胞株行反复裸鼠体内接种,是建立肺癌脑转移实验动物模型的可行方法.     

Two radiation regimens and prognostic factors for brain metastases in nonsmall cell lung cancer patients

BACKGROUND: Nonsmall cell lung cancer (NSCLC) patients with brain metastases usually receive whole-brain radiotherapy (WBRT). Most of these patients survive for only a few months. A short course of WBRT would be preferable to longer regimens if it could provide similar survival. This retrospective study of NSCLC patients compared longer treatment programs with short-course WBRT with 5 x 4 Gy given during 5 days. METHODS: Data from 404 NSCLC patients treated with WBRT for brain metastases were retrospectively analyzed. The 140 patients who received 5 x 4 Gy given in 5 days were compared for survival with 264 patients who received either 10 x 3 Gy given in 2 weeks or 20 x 2 Gy given in 4 weeks. Seven further potential prognostic factors were investigated for survival including age, sex, Karnofsky performance score (KPS), number of brain metastases, extracranial metastases, interval from tumor diagnosis to WBRT, and RPA (recursive partitioning analysis) class. RESULTS: The WBRT regimen was not associated with survival (P = .55). On multivariate analysis, age < 60 years (vs > or =60 years, P = .020), KPS > or =70 (vs KPS < 70, P < .001), interval from tumor diagnosis to WBRT > 12 months (vs < or =12 months, P = .007), no extracranial metastases (P < .001), and RPA class 1 (vs RPA class 2 vs RPA class 3, P = .007) were significantly associated with improved survival. CONCLUSIONS: Short-course WBRT with 5 x 4 Gy appeared preferable for most NSCLC patients, as it was associated with survival similar to longer WBRT programs, and the short course was less time consuming.     

The role of EGFR inhibitors in nonsmall cell lung cancer

PURPOSE OF REVIEW: The epidermal growth factor receptor is a cell membrane receptor that plays a key role in cancer development and progression. Ligand-activated epidermal growth factor receptor-dependent signaling is involved in cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Targeting the epidermal growth factor receptor represents a promising molecular approach in cancer treatment. Several antiepidermal growth factor receptor agents are in clinical development. This review focuses on the available clinical data on epidermal growth factor receptor-targeting drugs in the treatment of nonsmall cell lung cancer. RECENT FINDINGS: Three drugs are currently in phase 2 and phase 3 development as single agents or in combination with other anticancer therapies in nonsmall cell lung cancer patients: cetuximab (Erbitux), a chimeric human-mouse monoclonal IgG1 antibody that blocks ligand binding and functional epidermal growth factor receptor activation; and erlotinib (Tarceva) and gefitinib (Iressa), two orally bioavailable, small-molecule epidermal growth factor receptor inhibitors of tyrosine kinase enzymatic activity that prevent epidermal growth factor receptor autophosphorylation and activation. Single-agent gefitinib treatment has determined a 10 to 20% response rate and a 30 to 50% symptom improvement in previously treated, chemotherapy-refractory advanced nonsmall cell lung cancer patients. Gefitinib has been the first epidermal growth factor receptor-targeting agent to be registered as an anticancer drug in several countries, including Japan, Australia, and the United States, for the third-line treatment of chemoresistant nonsmall cell lung cancer patients. SUMMARY: Antiepidermal growth factor receptor has shown promising antitumor activity in nonsmall cell lung cancer patients with a mild toxicity profile. However, a series of important clinical issues such as selection of potentially responsive patients and optimal combination with conventional anticancer treatments needs to be addressed to use these drugs better in lung cancer.     

Inactivation of LLC1 gene in nonsmall cell lung cancer

Serial analysis of gene expression studies led us to identify a previously unknown gene, c20orf85, that is present in the normal lung epithelium but absent or downregulated in most primary nonsmall cell lung cancers and lung cancer cell lines. We named this gene LLC1 for Low in Lung Cancer 1. LLC1 is located on chromosome 20q13.3 and has a 70% GC content in the promoter region. It has 4 exons and encodes a protein containing 137 amino acids. By in situ hybridization, we observed that LLC1 message is localized in normal lung bronchial epithelial cells but absent in 13 of 14 lung adenocarcinoma and 9 out of 10 lung squamous carcinoma samples. Methylation at CpG sites of the LLC1 promoter was frequently observed in lung cancer cell lines and in a fraction of primary lung cancer tissues. Treatment with 5-aza deoxycytidine resulted in a reduced methylation of the LLC1 promoter concomitant with the increase of LLC1 expression. These results suggest that inactivation of LLC1 by means of promoter methylation is a frequent event in nonsmall cell lung cancer and may play a role in lung tumorigenesis.     

Implications of key trials in advanced nonsmall cell lung cancer

Many different targeted therapies with varying mechanisms of action have been added to standard first‐line chemotherapy doublets in an effort to improve survival of patients with advanced nonsmall cell lung cancer (NSCLC). Only 2 targeted therapies—bevacizumab and cetuximab—have been associated with superior survival in phase 3 first‐line studies. For both agents, the decision to enter phase 3 was based on results from randomized phase 2 trials, unlike other targeted therapies where the decision was made using either phase 1 or single study arm phase 2 results. There is also mounting evidence that patient selection will play a key role in the successful development of any targeted agent. Bevacizumab is indicated for patients with nonsquamous NSCLC who do not have certain comorbidities. Use of cetuximab is not restricted by safety factors, but may be focused on patients whose tumors are epidermal growth factor receptor (EGFR)‐dependent; whether EGFR expression or absence of KRAS mutations are appropriate markers is still under study. By including randomized phase 2 trials in the development pathway, and by improving patient selection for individual agents (enriching trials with patients most likely to respond), it may be possible to enhance the success rate of future phase 3 clinical trials and, in turn, define future clinical practice with improved patient outcomes. Cancer 2010. © 2010 American Cancer Society.