Seizure prophylaxis in patients with brain tumors: a meta-analysis

OBJECTIVE: To assess whether antiepileptic drugs (AEDs) should be prescribed to patients with brain tumors who have no history of seizures. METHODS: We performed a meta-analysis of randomized controlled trials (1966-2004) that evaluated the efficacy of AED prophylaxis vs no treatment or placebo to prevent seizures in patients with brain tumors who had no history of epilepsy. Summary odds ratios (ORs) were calculated using a random-effects model. Three subanalyses were performed to assess pooled ORs of seizures in patients with primary glial tumors, cerebral metastases, and meningiomas. RESULTS: Of 474 articles found in the initial search, 17 were identified as primary studies. Five trials met inclusion criteria: patients with a neoplasm (primary glial tumors, cerebral metastases, and meningiomas) but no history of epilepsy who were randomized to either an AED or placebo. The 3 AEDs studied were phenobarbital, phenytoin, and valproic acid. Of the 5 trials, 4 showed no statistical benefit of seizure prophylaxis with an AED. Meta-analysis confirmed the lack of AED benefit at 1 week (OR, 0.91; 95% confidence interval [CI], 0.45-1.83) and at 6 months (OR, 1.01; 95% CI, 0.51-1.98) of follow-up. The AEDs had no effect on seizure prevention for specific tumor pathology, including primary glial tumors (OR, 3.46; 95% CI, 0.32-37.47), cerebral metastases (OR, 2.50; 95% CI, 0.25-24.72), and meningiomas (OR, 0.62; 95% CI, 0.10-3.85). CONCLUSIONS: No evidence supports AED prophylaxis with phenobarbital, phenytoin, or valproic acid in patients with brain tumors and no history of seizures, regardless of neoplastic type. Subspecialists who treat patients with brain tumors need more education on this issue. Future randomized controlled trials should address whether any of the newer AEDs are useful for seizure prophylaxis.     

幕上肿瘤伴发癫(癎)的精确定位和手术疗效分析

目的 探讨幕上肿瘤伴发癫(癎)的精确定位价值和手术治疗效果,研究肿瘤与致(癎)灶的关系.方法 对121例(胶质瘤Ⅰ级15例、Ⅱ级35例、Ⅲ～Ⅳ级12例,脑膜瘤32例,脑转移瘤10例,海绵状血管瘤15例,室管膜瘤2例)临床上以癫(癎)为首发症状的幕上肿瘤患者术前、术后癫(癎)发作情况等,临床资料进行回顾性分析.结果 采用术前影像和脑电结合定位、术中皮层脑电再次定位的方法,对肿瘤和癫(癎)灶同时切除,无手术死亡.癫(癎)发生率最高在额叶,最低在枕叶.癫(癎)灶与肿瘤的关系:位于同一部位者50例;致(癎)灶位于肿瘤一侧或近旁者28例;致(癎)灶位于肿瘤远隔部位(＞2 cm)25例;检测不到致痫灶者18例.失访18例,103例随访1～9年,31例术后早期仍有小发作,83例不再服抗癫(癎)药物癫(癎)症状完全消除.结论 在幕上肿瘤伴发癫(癎)患者中,致(癎)灶与肿瘤灶存在一定的差异性.在开颅切除肿瘤的同时必须明确致(癎)灶的位置和范围,一并切除才能达到良好的手术效果.     

Quantitative protein expression of blood‐brain barrier transporters in the vasculature of brain metastases of patients with lung and breast cancer

This study determined absolute transporter protein abundances in isolated microvessels of human noncancerous cerebral cortex as well as brain metastases of patients with lung and breast cancer, using a validated targeted proteomics approach. As compared with those in microvessels of noncancerous cerebral cortex, the median protein abundances of glucose transporter 1 (a brain endothelial marker) and sodium‐potassium pump (Na/K ATPase, a plasma membrane marker) were decreased by ~ 80% in brain metastasis microvessels. The major efflux transporters (ABCB1 and ABCG2) fell to undetectable in microvessels of more than 80% of brain metastasis specimens. Monocarboxylate transporter 1 was undetectable in microvessels of more than 80% of brain metastases, whereas large neutral amino acid transporter 1 levels remained unchanged. In conclusion, the integrity of the physical and biochemical barrier with respect to transporter protein expression is largely disrupted in brain metastasis tumor vasculatures. Differential transporter protein abundances at the blood‐brain barrier and blood‐brain tumor barrier provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Systemic chemotherapy for brain metastases is controversial, at least partly due to the incomplete understanding of the blood‐brain barrier (BBB) and blood‐brain tumor barrier (BBTB) with respect to transporter protein expression and function.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study determined the absolute protein abundances of major BBB transporters in isolated microvessels of brain metastases from lung and breast cancer patients as well as non‐cancerous brain cortex from primary or metastatic brain cancer patients.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study complemented our previous knowledge on transporter expression in microvessels of human normal brain cortex and glioblastoma, which collectively provided a comprehensive dataset on the quantitative protein expression of BBB transporters in the vasculatures of human normal brain, primary and metastatic brain tumors.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Differential transporter protein abundances at the BBB and BBTB provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.     

Epidemiology, diagnosis, and treatment of patients with metastatic cancer and high-grade gliomas of the central nervous system.

Cancer is the hyperactive state of cell growth in which the multiplication and division of cells occur abnormally.Malignant cancer to the brain frequently begins and ends with the loss of self or quality of life. Cancer of the central nervous system can be in the form of a primary or secondary brain tumor commonly known as metastatic cancer. Primary brain tumors can be benign or malignant on the basis of the cell type or location within the brain. Metastatic cancer has a primary source of origin, from which it has traveled to the brain by direct extension (tumors arising from the skull or vertebral column), or most commonly by hematogenous spread (through the blood supply, lymphatic system, or cerebral spinal fluid). As the cancer grows, the individual can experience headache, seizures, or focal neurologic deficits, all impinging on quality of life. This article addresses malignant central nervous system cancer including metastatic cancer and malignant gliomas (anaplastic astrocytoma, grade III, and glioblastoma multiforme, grade IV). Epidemiology, diagnostic workup, treatment, and outcome also are reviewed.     

肺癌合并孤立性脑转移的外科治疗效果的分析

目的比较肺癌合并孤立性脑转移患者原发病灶切除及不同方法处理脑部转移灶的临床疗效。方法回顾性分析2004年1月至2008年6月在中山大学附属第一医院收治的37例非小细胞肺癌合并孤立性脑转移的患者的临床资料,其中21例患者接受开颅摘除脑转移瘤＋肺部原发灶的根治性切除治疗（开颅组）;16例患者接受γ-刀照射脑转移瘤＋肺部原发灶根治性切除治疗（γ-刀组）。观察两组患者治疗后的中位生存时间和1年生存率情况。结果中位随访时间20个月（18～26个月）。开颅组和γ-刀组的中位生存时间分别为11．8个月和12．6个月,1年生存率分别为57．14％（12／21）和56．25％（9／16）,但两组的生存曲线无统计学意义（P〉0．05）。结论对于肺癌合并孤立性脑转移灶的患者应积极外科处理;至于脑部转移灶的处理,γ-刀的使用具有创伤小,疗程短的优越性。     

Bone metastasis as the first manifestation of lung cancer

Bone metastasis usually occurs late in the course of the disease, but in some patients it is the first manifestation of lung cancer. To evaluate the characteristics of patients with bone metastasis as a first manifestation of lung cancer, the medical records of 1063 patients with lung cancer between 1976 and 2001 were reviewed retrospectively. Twenty-four (2.3%) lung cancer patients presented symptoms of bone metastasis as a first manifestation; 11 patients had bone metastasis as the only site of spread in lung cancer; 16 had adenocarcinoma; five had a primary lesion <30 mm, and nine had N0-1 disease. Patients with sole bone metastasis did not have a more favourable survival rate than patients with bone and other systemic metastases (p=0.2938). Whether metastasis is the first manifestation of lung cancer or not, the occurrence of bone metastasis generally means a poor prognosis.     

磁敏感加权成像在脑胶质瘤鉴别诊断、术前病理分级及术中的应用

  目的  探讨磁敏感加权成像（SWI）在脑胶质瘤鉴别诊断、术前病理分级及手术指导中的应用。  方法  回顾性分析新疆维吾尔自治区人民医院2018年10月~2021年10月经手术及组织病理学检查证实为脑胶质瘤（n=64）、单发脑转移瘤（n=15）和颅内淋巴瘤（n=15）的患者的临床资料。以病理结果作为金标准,将脑胶质瘤患者按照世界卫生组织肿瘤分类标准分为低级别组（n= 27）和高级别组（n=37）,所有患者均通过SWI检测,进行瘤内磁敏感信号强度（ITSS）分级评估以及肿瘤实质区与瘤周水肿区相对脑血容量（rCBV）值测定,比较不同肿瘤类型差异,并通过ROC曲线评估其在高级别与低级别脑胶质瘤中的鉴别价值。  结果  高级别脑胶质瘤与单发脑转移瘤ITSS分级、肿瘤实质区rCBV值的差异无统计学意义（P > 0.05）;高级别脑胶质瘤周水肿区rCBV值高于单发脑转移瘤（P < 0.05）;高级别脑胶质瘤ITSS分级程度低于淋巴瘤,血管评分高于淋巴瘤（P < 0.05）;高级别胶质瘤ITSS分级高于低级别胶质瘤,肿瘤实质区rCBV值高于低级别胶质瘤（P < 0.05）;Spearman相关性分析结果显示,胶质瘤分级与ITSS分级、rCBV值呈正相关关系（r=0.728、0.851,P < 0.05）;ITSS分级评估脑胶质瘤高级别ROC曲线下面积为0.894,敏感度、特异性、准确度分别为81.08%、85.19%、82.81%;rCBV值评估脑胶质瘤高级别ROC曲线下面积为0.937,敏感度、特异性、准确度分别为91.89%、88.89%、90.63%;64例脑胶质瘤患者,和常规序列相比,SWI序列对于肿瘤边界的显示更为清晰,同时可呈现肿瘤微小血管病变信息,胶质瘤肿瘤实质区rCBV值均高于瘤周水肿区rCBV值（P < 0.05）。  结论  SWI有助于高级别胶质瘤的鉴别诊断,对于胶质瘤低级别与高级别的评估效能较高,可在一定程度上指导术中脑胶质瘤切除。      

KRAS, NRAS, PIK3CA exon 20, and BRAF genotypes in synchronous and metachronous primary colorectal cancers diagnostic and therapeutic implications

Targeted therapy of advanced colorectal carcinoma (CRC) necessitates KRAS genotyping. Because we were interested in diagnostic and therapeutic consequences, we studied the KRAS, NRAS, PIK3CA exon 20, and BRAF genotypes in synchronous and metachronous primary CRCs; in addition, we studied their available metastases. We studied 21 patients with 43 synchronous and 2 metachronous adenocarcinomas of the colorectum (n = 20) and stomach (n = 1). Five patients had liver metastases and one had a distant lymph node metastasis. Genomic DNA was extracted from microdissected tumor tissue. The DNA was analyzed by Sanger sequencing and pyrosequencing. Fifty-seven different neoplastic lesions were genotyped, showing 18 (31.6%) KRAS, 2 (3.5%) NRAS, and 7 (12.3%) BRAF mutations, distributed among 10 (47.6%), 1 (4.8%), and 5 (23.8%) of the patients. An identical genotype of all synchronous primary CRCs was found only in 7 (35%) of the patients; the remainder had dissimilar genotypes in various combinations. Interestingly, a single patient had an unknown KRAS genotype (c.37_39dupGGC). Six patients with 13 primary carcinomas had distant metastases. In three of these patients, the metastasis shared the genotype only with one of the primary tumors, because the other primary tumors had another genotype. Synchronous and metachronous primary CRCs of the same patient have variable KRAS, NRAS, and BRAF genotypes. When metastases occur in these patients, the genotype has diagnostic and therapeutic implications and should be determined from the simultaneous or metachronous distant metastases.     

氢质子磁共振波对颅内转移瘤与胶质瘤鉴别及生存分析的意义

目的探讨氢质子磁共振波谱(1H magnetic resonance spectroscopy,1H-MRS)鉴别高级别脑胶质瘤与肺癌脑转移瘤的临床鉴别诊断及其对生存预测的应用价值。材料与方法回顾性分析经手术病理确诊及经l H-MRS检查的高级别脑胶质瘤患者36例和肺癌脑转移瘤患者43例,并计算1H-MRS检查的N-乙酰天门冬氨酸(N-acetylaspartate,NAA)/胆碱(Choline,Cho)、NAA/肌酸(Creatine,Cr)和Cho/Cr的比值。根据回访记录的生存时间,采用Cox风险模型进行多因素分析筛选出对肺癌脑转移瘤患者生存具有独立预测作用的因素。结果高级别脑胶质瘤和肺癌脑转移瘤的瘤周组织的Cho/NAA和Cho/Cr比值差异存在显著性(P0.01),经Cox多因素回归分析肺癌脑转移瘤外周Cho/Cr是生存时间的独立预测因素(P0.05)。结论肺癌脑转移瘤和高级别脑胶质瘤瘤周组织间Cho/NAA和Cho/Cr比值的差异可作为1H-MRS鉴别高级别脑胶质瘤和肺癌脑转移瘤的特征,肺癌脑转移瘤外周Cho/Cr可能对评估患者生存时间有一定意义。     

磁共振弥散加权成像对脑肿瘤瘤周水肿的临床应用

目的探讨瘤(灶)周水肿的磁共振弥散加权成像(DWI)表现在脑肿瘤诊断方面的临床应用价值.方法对73例脑肿瘤(胶质瘤40例,转移瘤20例,脑膜瘤13例)、3例脑脓肿及2例炎性肉芽肿患者进行常规MRI及DWI检查.对照测量病变的实质部分、周围水肿区以及正常脑组织的表观弥散系数(ADC)值,并分析实质部分及水肿区的相对ADC值(rADC).对于瘤周水肿直径＞1 cm者,将水肿区域划分为近侧、远侧瘤周.结果高级别胶质瘤与低级别胶质瘤、转移瘤、脑膜瘤、炎性病变之间的近侧瘤(灶)周水肿rADC值存在差异.各病变远侧水肿区之间的rADC值无差别.高级别胶质瘤的近侧瘤周水肿区rADC值低于远侧;低级别胶质瘤近、远侧瘤周水肿的rADC不能区分;转移瘤、脑膜瘤、炎性病变近侧瘤(灶)周水肿区rADC值高于远侧.结论脑肿瘤近侧水肿区DWI检查的rADC值有助于胶质瘤级别鉴定和与其他肿瘤及炎性病变的鉴别.高级别胶质瘤近侧瘤周水肿区rADC值低于远侧,而在低级别胶质瘤、转移瘤、脑膜瘤和炎性病变却相反.     

Effect of sevoflurane on spontaneous brain bioelectrical activity in neurosurgical patients

The present study was undertaken to evaluate the effects of sevoflurane on spontaneous brain bioelectrical activity in neurosurgical patients. Forty patients treated at the Research Institute of Neurosurgery underwent a neurophysiological examination. No epileptic syndrome was revealed in the clinical picture in 10 patients (a control group), the remaining 30 patients had a history of varying epileptic seizures of different degrees and frequency. Sevoflurane causes a relative acceleration of epileptiform activity synchronization, as evidenced by EEG, which is not a contraindication to the use of this drug in patients with cerebral organic lesion of various genesis with a history of epileptic syndrome and fails to induce clinically significant EEG epileptiform manifestations in patients without epilepsy. In patients with cerebrovascular abnormalities (arteriovenous malformation, cavernous angiomas) who have a history of paroxysmal conditions, inhalational sevoflurane anesthesia can be performed in combination with anticonvulsants (benzodiazepines) during an operation.     

高频彩超结合血管内皮因子C对乳腺癌腋窝淋巴结转移的诊断价值

目的探讨彩色多普勒超声(CDFI)结合血管内皮生长因子C(VEGF-C)对浸润性乳腺癌腋窝淋巴结转移的诊断价值。方法应用免疫组化技术VEGF-C结合CDFI声像图特点对59例浸润性乳腺癌患者腋窝淋巴结状态进行比较研究。结果乳腺癌腋窝淋巴结转移组较未转移组肿瘤内彩色血流信号丰富(P<0.05);>2cm组较≤2cm组肿瘤内彩色血流信号丰富(P<0.05)。淋巴结转移组较未转移组VEGF-C阳性表达率明显增高(P<0.05)。结论浸润性乳腺癌CDFI肿瘤内彩色血流信号丰富程度及VEGF-C阳性表达率与腋窝淋巴结发生转移密切相关。     

颅脑肿瘤多体素^1H-MRS特征与病理对照研究

目的研究颅脑肿瘤的磁共振质子波谱（^1H-MRS）的表现及其临床诊断与鉴别诊断价值。方法50例行^1H-MRS检查的不同组织类型来源颅脑肿瘤患者，术后均经病理明确诊断，观察和测量肿瘤和对侧正常组织的N-乙酰天冬氨酸（NAA）、肌酸（Cr）、复合胆碱（Cho）、乳酸（Lac）、脂质（Lip）峰值，计算肿瘤NAA／Cr、Cho／Cr、NAA／Cho以及肿瘤NAA／正常NAA、肿瘤Cho／正常Cho、肿瘤Cr／正常CT的比率。结果颅脑肿瘤Cr下降，Cho升高，但不同组织类型肿瘤的Cr、Cho变化无显著差异。脑肿瘤NAA下降明显，其中不同组织类型中脑膜瘤、胶质瘤相比变化无显著差异，但均明显低于听神经瘤和转移瘤（P〈0．05）。胶质瘤的NAA／Cr明显低于转移瘤和听神经瘤，P值分别为0．015、0．028。各肿瘤的Cho／Cr无显著差异。结论^1H-MRS是研究肿瘤代谢的有效方法，肿瘤NAA／正常NAA、NAA／Cr有助于颅脑肿瘤的诊断和鉴别诊断。     

Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems

Purpose

To document the risk of skeletal complications in patients with bone metastases from breast cancer (BC), lung cancer (LC), or prostate cancer (PC) in routine clinical practice.

Methods

We used data from two large US health systems to identify patients aged ≥18 years with primary BC, LC, or PC and newly diagnosed bone metastases between January 1, 1995 and December 31, 2009. Beginning with the date of diagnosis of bone metastasis, we estimated the cumulative incidence of skeletal-related events (SREs) (spinal cord compression, pathologic fracture, radiation to bone, bone surgery), based on review of medical records, accounting for death as a competing risk.

Results

We identified a total of 621 BC, 477 LC, and 721 PC patients with newly diagnosed bone metastases. SREs were present at diagnosis of bone metastasis in 22.4, 22.4, and 10.0 % of BC, LC, and PC patients, respectively. Relatively few LC or PC patients received intravenous bisphosphonates (14.8 and 20.2 %, respectively); use was higher in patients with BC, however (55.8 %). In BC, cumulative incidence of SREs during follow-up was 38.7 % at 6 months, 45.4 % at 12 months, and 54.2 % at 24 months; in LC, it was 41.0, 45.4, and 47.7 %; and in PC, it was 21.5, 30.4, and 41.9 %. More than one half of patients with bone metastases had evidence of SREs (BC: 62.6 %; LC: 58.7 %; PC: 51.7 %), either at diagnosis of bone metastases or subsequently.

Conclusions

SREs are a frequent complication in patients with solid tumors and bone metastases, and are much more common than previously recognized in women with BC.     

脑梗死后早发性癫痫发作的发生率及其影响因素分析

[目的]了解脑梗死后早发性癫痫发作的发生率并分析其影响因素.[方法]对426例脑梗死患者脑梗死后早发性癫痫发作的发生情况进行回顾性分析;应用统计学方法分析脑梗死后症状性癫痫与各影响因素的关系.[结果]426例患者中有早发性癫痫发作的患者56例,占13.15% ,发作类型以全身强直-阵挛性发作多见.单因素分析显示,皮质脑梗死、复发脑梗死、电解质紊乱患者易发生脑梗死后早发性癫痫发作;Logistic回归分析显示,梗死部位、梗死次数和电解质情况与脑梗死后早发性癫痫发作有关,其中皮质脑梗死为脑梗死后早发性癫痫发作的独立危险因素.[结论]脑梗死后早发性癫痫发作的发生率较高,皮质脑梗死、复发脑梗死以及电解质紊乱是脑梗死后早发性癫痫发作的影响因素,皮质脑梗死为独立的危险因素.     

104例皮肤转移性癌肿的临床病理分析

１０４例皮肤转移性癌肿作临床病理分析，其原发肿瘤与皮肤转移瘤均经病理证实。结果朱发肿瘤在乳腺２８例，肺２１例，胃１４例，结肠１１例，肾、食道，卵巢在宫颈各３例，其它少数部位８例，黑色素瘤１０例，而最常见转移到皮肤的癌肿在男性为肺癌，胃癌及黑色素瘤，在女性为乳腺癌、结肠癌及肺癌。     

Breast cancer: metastatic patterns and their prognosis

From 1969 to 1977, metastatic disease developed in 145 of the 558 patients treated for breast cancer at the University of Maryland Medical System. The most common first site of distant spread was bone (51%), followed by lung (17%), brain (16%), and liver (6%). The remaining 10% of patients had multiple metastatic sites. Fewer than 10% of the entire group received adjuvant chemotherapy after primary treatment. When metastatic disease appeared, most patients had palliative systemic chemotherapy and/or irradiation. In general, patients with initially negative axillary nodes had a longer median time until relapse (development of metastatic disease) and a longer survival time after diagnosis of metastases than patients with initially positive nodes. Liver was the least common initial metastatic site; while liver metastasis was seen only in patients with positive axillary nodes, it carried the worst prognosis. The overall median survival time after metastasis was 12 months for bone and lung lesions, three months for brain lesions, and only one month for liver metastasis. The median survival of patients with multiple metastatic sites was 7.5 months. No correlation was found between time until relapse and survival after metastasis. Patients in whom distant metastases developed relatively soon after the initial diagnosis had the same postmetastatic prognosis as patients whose disease metastasized later. No correlation was found between age at initial diagnosis and metastasis-free interval or survival after metastasis.     

DSC-MRI鉴别诊断胶质母细胞瘤、单发脑转移瘤及脑淋巴瘤

目的 探讨动态磁敏感对比增强磁共振成像（DSC-MRI）鉴别诊断胶质母细胞瘤、单发脑转移瘤及脑淋巴瘤的价值。方法 回顾性分析经活检或术后病理证实的胶质母细胞瘤患者17例、单发脑转移瘤患者15例、淋巴瘤患者17例。患者术前均接受MRI常规平扫、增强及DSC-MRI扫描,获得脑血容量（CBV）伪彩图及时间-信号强度曲线,分别测量瘤体、瘤周水肿区及对侧正常白质区的CBV值,计算相对脑血容量（rCBV）值和瘤体的信号强度恢复百分比（PSR）。应用ROC曲线分析各指标对3种肿瘤的诊断效能。结果 胶质母细胞瘤、单发脑转移瘤及脑淋巴瘤均表现为肿瘤实性区域明显强化伴瘤周水肿。瘤体rCBV除胶质母细胞瘤与单发脑转移瘤无差异外,余两两比较差异均有统计学意义（P均<0.05）;瘤周rCBV除单发脑转移瘤与淋巴瘤无差异外,余两两比较差异均有统计学意义（P均<0.05）;瘤体PSR值除胶质母细胞瘤与单发脑转移瘤无差异外,余两两比较差异均有统计学意义（P均<0.05）。ROC曲线示瘤体PSR为鉴别淋巴瘤及非淋巴瘤的最佳指标,敏感度、特异度分别为100%和81.3%;瘤周rCBV为鉴别胶质母细胞瘤及单发脑转移瘤的最佳指标,敏感度、特异度分别为94.1%和86.7%。结论 rCBV和PSR结合可提高鉴别诊断3种脑肿瘤的效能。     

Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of angiopep-2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors

GRN1005 is a novel peptide-drug conjugate composed of paclitaxel covalently linked to a peptide, angiopep-2, that targets the low-density lipoprotein receptor-related protein 1. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until grade 2 toxicity, then 3 + 3 design) received intravenous GRN1005 at escalating doses between 30 and 700 mg/m(2) once in every 21 days. In the maximum tolerated dose (MTD) expansion group, patients were required to have brain metastases. Fifty-six patients received GRN1005, including 41 with brain metastases (median number of prior therapies = 4). MTD was 650 mg/m(2); the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. Pharmacokinetics was dose linear and the mean terminal-phase elimination half-life was 3.6 hours. No evidence of accumulation was observed after repeat dosing. No anti-GRN1005 antibodies were detected. Five of the 20 patients (25%) dosed at 650 mg/m(2) (MTD), three of whom had previous taxane therapy, achieved an overall partial response (breast, n = 2; non-small cell lung cancer, n = 2; and ovarian cancer, n = 1); responses in all five patients were also accompanied by shrinkage of brain lesions (-17% to -50%). In addition, six patients (11%; doses 30-700 mg/m(2)) experienced stable disease that lasted 4 months or more. GRN1005 was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors, including those who had brain metastases and/or failed prior taxane therapy.