贝伐单抗一线治疗胶质母细胞瘤的Meta分析

目的 采用循证医学的方法,评价贝伐单抗一线治疗胶质母细胞瘤的疗效及安全性。方法检索PubMed、Embase、Cochrane图书馆、中国期刊全文数据库CNKI及中国生物医学文献数据库;对符合纳入标准的文献进行数据汇总,采用Meta-Analyst Beta 3.13进行数据分析。结果 共检索到相关文献78篇,排除66篇,最终纳入12项临床试验,共计837例患者。通过Meta分析对数据进行合并,其结果显示：所有应用贝伐单抗治疗的患者6月无疾病进展生存率为84.5%（95%CI:78.1~89.3）,12月无疾病进展生存率为55.1%（95%CI:48.0~61.9）,1年总生存率为76.0%（95%CI:62.5~85.7）,2年总生存率为38.4%（95%CI:32.5~44.7）。经比较分析示：贝伐单抗联合RT+TMZ组与在此基础上增加其他药物组之间患者的无进展生存期和总生存期无明显差异。常见不良反应为：血小板减少、血栓/栓塞、疲劳、脑卒中、粒细胞减少、感染等,不同治疗组织之间不良反应的发生率无明显差异。结论 贝伐单抗联合标准方案治疗能够延长患者的无进展生存期,但并不能改善患者的总生存期。在贝伐单抗联合标准方案的基础上再增加其他药物治疗,未能明显改善患者的无进展生存期和总生存期。     

贝伐单抗治疗胶质母细胞瘤的进展

贝伐单抗作为全球第一个抗血管生成的单克隆抗体,2009年被FDA批准用于胶质母细胞瘤的挽救治疗,之后贝伐单抗治疗新诊断的胶质母细胞瘤成为众多学者研究的焦点,但最新的研究结果并不支持它在胶质母细胞瘤的一线治疗中应用。     

贝伐单抗治疗复发性胶质母细胞瘤的研究进展

胶质母细胞瘤恶性程度高,局部浸润性强,复发率高。近年研究表明,血管增殖在胶质母细胞瘤的进展过程中起重要作用。贝伐单抗（bevacizumab）可以特异性阻断血管内皮生长因子（vascularendothelialgrowthfactor,VEGF）与其受体结合,抑制肿瘤血管形成,从而达到抗肿瘤的目的。贝伐单抗在复发性胶质母细胞瘤中的作用逐渐引起人们的关注。     

贝伐珠单抗联合紫杉醇治疗复发性卵巢癌疗效分析

目的 观察贝伐珠单抗联合紫杉醇治疗复发性卵巢癌的疗效和不良反应.方法 35例复发性卵巢癌患者应用贝伐珠单抗联合紫杉醇作为二线或多线治疗.结果 35例患者均可进行疗效评价,有效率为54.29%,疾病控制率为82.86%.不良反应主要有骨髓抑制、恶心呕吐、高血压、蛋白尿等,大多为轻度.结论 贝伐珠单抗联合紫杉醇治疗复发性卵巢癌安全有效,患者可耐受,是复发性卵巢癌可选择的治疗方案之一.     

贝伐珠单抗联合替莫唑胺剂量密度方案治疗复发胶质瘤的疗效分析

目的:评价贝伐珠单抗联合替莫唑胺剂量密度方案治疗复发胶质瘤的疗效及不良事件。方法:回顾性分析20例接受过贝伐珠单抗联合替莫唑胺剂量密度方案治疗的复发胶质瘤患者的临床资料并进行生存随访。依据RANO标准评价客观疗效,应用Kaplan-Meier 法进行生存分析,不良事件评价依据CTCAE 4.0版标准。结果:20例复发胶质瘤患者的临床获益率和客观反映率可达到85%和60%,中位PFS和中位OS分别为3个月（1.5~11个月）和6.5个月（3~15个月）。主要不良事件为高血压。结论:贝伐珠单抗联合替莫唑胺剂量密度方案治疗复发胶质瘤安全有效,且耐受性良好。     

贝伐珠单抗治疗恶性腹腔积液的研究进展

恶性腹腔积液是晚期肿瘤患者常见的并发症,不仅严重影响患者的生活质量,还提示预后较差.目前针对恶性腹腔积液的全身治疗有限盐利尿、补充白蛋白、治疗原发肿瘤等,还有在此基础上进行腹腔穿刺引流及腹腔药物灌注等局部治疗.血管内皮生长因子(VEGF)是恶性腹腔积液形成的关键介质,其主要通过调节血管生成,增加血管通透性来诱导腹腔积液...     

贝伐珠单抗在结直肠癌治疗中的应用

近年来,随着对肿瘤生物学认识的深入,以贝伐珠单抗、西妥昔单抗为代表的分子靶向治疗药物正逐渐丰富着晚期结直肠癌的治疗选择.贝伐珠单抗是一种人源化、人鼠嵌合抗血管内皮生长因子的单克隆抗体,是第一个被美国FDA批准用于治疗晚期结直肠癌患者的抗血管生成药物,以贝伐珠单抗为基础进行的临床研究也证实了它能改善晚期结直肠癌患者的生存期.全文通过回顾近年来发布的结直肠癌治疗领域有关贝伐珠单抗的临床研究,对其在晚期结直肠癌一线、二线和维持治疗以及在结直肠癌术后辅助治疗领域中的应用做一系统综述.     

紫杉醇联合贝伐珠单抗治疗卵巢癌的效果分析

目的探讨紫杉醇联合贝伐珠单抗化疗治疗卵巢癌的临床效果。方法按照化疗方案不同将收治的87例卵巢癌患者分为实验组(45例)和对照组(42例),实验组患者给予紫杉醇联合贝伐珠单抗化疗,对照组给予环磷酰胺、紫杉醇联合洛铂化疗,比较两组患者近期疗效、不良反应以及3年生存情况。结果实验组患者总有效率显著高于对照组,差异具有统计学意义(P<0.05);实验组3年生存率显著高于对照组,差异具有统计学意义(P<0.05);两组患者均发生不同程度骨髓抑制反应,采取对症治疗后缓解,两组间不良反应发生率比较,差异无统计学意义(P>0.05)。结论紫杉醇联合贝伐珠单抗化疗治疗卵巢癌临床疗效显著,3年远期生存率较环磷酰胺、紫杉醇联合洛铂化疗方案的更高,但紫杉醇用药时需要注意预防过敏。     

超选择性颅内动脉灌注贝伐珠单抗治疗复发恶性脑胶质瘤的疗效及安全性

目的:观察超选择性颅内动脉灌注贝伐珠单抗治疗复发恶性脑胶质瘤的疗效及安全性。方法:纳入2017年10月至2020年11月在我院神经外科接受超选择性颅内动脉灌注贝伐珠单抗治疗的11例复发恶性脑胶质瘤患者,观察治疗后的无进展生存期、Karnofsky评分及不良反应,随访终点为肿瘤再次出现复发或转移。结果:经2个周期治疗后,11例复发恶性脑胶质瘤患者的疾病控制和客观反应人数分别为10例和8例,患者Karnofsky评分较治疗前显著提高(P<0.05)。中位无进展生存时间为6个月,11例患者中有1例出现皮肤过敏,1例患者出现白细胞减少。结论:采用超选择性颅内动脉灌注贝伐珠单抗治疗复发恶性脑胶质瘤安全、有效,值得临床进一步推广应用。     

Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients

Journal of Neuro-Oncology - The combination of lomustine and bevacizumab is a commonly used salvage treatment for recurrent glioblastoma (GBM). We investigated the toxicity and efficacy of...     

Stereotactic radiosurgery and bevacizumab for recurrent glioblastoma multiforme

Despite contemporary surgery, image-guided radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) persists or relapses in nearly all patients, and tumors almost always recur locally. Management of recurrent GBM is variable, but approaches include best supportive care, reoperation, reirradiation, and/or systemic therapy. Promising novel therapies include antiangiogenic agents and stereotactic radiosurgery, which have cytotoxic effects on tumor microvasculature. Emerging data suggest the safety and efficacy of bevacizumab and radiosurgery either alone or in combination. This report presents the case of a man with locally recurrent GBM treated with stereotactic radiosurgery and concurrent bevacizumab, and reviews the preclinical and clinical data supporting this approach.     

Salvage therapy with single agent bevacizumab for recurrent glioblastoma

A retrospective evaluation of single agent bevacizumab in adults with recurrent glioblastoma (GBM) with an objective of determining progression free survival (PFS). There is no standard therapy for recurrent GBM after failure of alkylator-based chemotherapy. A total of 50 adults, ages 36–70 years (median 64), with recurrent GBM were treated. All patients had previously been treated with surgery, concurrent radiotherapy and temozolomide, post-radiotherapy temozolomide and in 34 patients, one salvage regimen (PCV: 21, cyclophosphamide: 13). A total of 13 patients underwent repeat surgery. Patients were treated at first or second recurrence with bevacizumab, once every 2 weeks, defined as a single cycle. Neurological evaluation was performed every 2 weeks and neuroradiographic assessment following the initial 2 cycles of bevacizumab and subsequently after every 4 cycles of bevacizumab. A total of 468 cycles of bevacizumab (median 2 cycles; range 1–30) was administered. Bevacizumab-related toxicity included fatigue (16 patients; 4 grade 3), leukopenia (9; 1 grade 3), anemia (5; 0 grade 3), hypertension (7; 1 grade 3), deep vein thrombosis (4; 1 grade 3) and wound dehiscence (2; 1 grade 3). 21 patients (42%) demonstrated a partial radiographic response and 29 (58%) progressive disease following 1–2 cycles of bevacizumab. Time to tumor progression ranged from 0.5 to 15 months (median: 1.0 months). Survival ranged from 2 to 17 months (median: 8.5 months). 6-month and 12-month PFS were 42% and 22% respectively. Single agent bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent alkylator-refractory GBM.     

Editor's choice: Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy

Background

The optimal timing to initiate bevacizumab (BV) therapy for recurrent glioblastoma (GBM) is currently unclear. To address this issue, we examined progression-free survival (PFS) and survival time (ST) in a large retrospective cohort of GBM patients treated with BV at different recurrences.

Methods

We identified 468 primary GBM patients who underwent biopsy or surgery followed by radiation therapy and temozolomide (RT/TMZ), and then received BV. PFS and ST were compared between patients stratified by the recurrence that BV was initiated (upfront, first recurrence, second recurrence, or 3+ recurrences). We also examined the effect on PFS and ST of the addition of chemotherapy to BV. In a larger cohort of GBM patients, we determined overall treatment continuation rates at each recurrence and identified variables predictive of inability to continue treatment.

Results

BV PFS was similar for all 3 recurrence groups (median, 4.1 months). There were no differences in BV ST (median, 9.8 months). The addition of chemotherapy to BV improved PFS but not ST. Analysis of treatment continuation rates indicated that the number of patients unable to undergo further treatments is modest, and that patients unable to tolerate BV delay can be identified by age ≥60 years and low extent of resection.

Conclusions

Deferred use of bevacizumab is not associated with diminished efficacy. Analysis of treatment continuation rates identified patients who may be unable to delay BV therapy. Our findings suggest that there is a fixed survival after BV initiation and that delayed BV treatment is preferable for most patients.     

Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure

There is no effective treatment for recurrent glioblastoma (GBM) after bevacizumab failure. Putative mechanisms of resistance to bevacizumab include increased pericyte coverage, mediated partly by platelet-derived growth factor receptor (PDGFR) signaling, and an infiltrative tumor growth pattern potentially dependent on SRC. We explored the efficacy of dasatinib, a SRC, BCR-ABL, c-KIT, EPHA2, and PDGFRβ inhibitor, in patients with recurrent GBM after bevacizumab failure. Adult patients with histologically confirmed GBM who failed bevacizumab therapy were treated with dasatinib 70–100 mg twice daily in combination with bevacizumab (n = 14), until tumor progression or unacceptable toxicity. Fourteen patients were treated. Median age was 55 years (range 32–66) and median KPS was 80 (range 50–90). All patients (100%) had glioblastomas. The median number of prior regimens was 4 (range from 2 to 6). Of the thirteen evaluable patients, none had a complete or partial response. Only one patient had stable disease after an 8 week interval. Median progression-free survival (PFS) was 28 days (95% confidence interval [CI] 26–35 days). Six month progression-free survival (PFS6) was 0%. Median overall survival (OS) was 78 days (95% CI 41–137 days). Treatment was moderately well-tolerated, although one patient sustained a grade 4 intracerebral hemorrhage. Dasatinib in conjunction with bevacizumab does not appear to have activity in patients with recurrent, heavily pretreated GBM.     

Molecular analysis of a recurrent glioblastoma treated with bevacizumab

We treated a case of recurrent glioblastoma (GBM) with bevacizumab and assessed its effect biologically. A 55-year-old man with a left frontal lobe GBM was experiencing recurrence 7 months postoperation. We administered bevacizumab concomitant with temozolomide (TMZ). Follow-up magnetic resonance imaging (MRI) showed dramatic but temporal tumor reduction; however, the patient died of re-recurrent disease 6 months after beginning bevacizumab. We obtained an autopsy and analyzed the detailed molecular change. In the autopsy specimen, the quantity of microvessels was significantly reduced. Vascular endothelial growth factor receptor (VEGFR) 1 and VEGFR2 were downregulated, most likely due to a negative feedback mechanism by blocking of VEGF signaling. Matrix metalloproteinase (MMP)-2 and membrane-type 1 MMP were upregulated, resulting in the higher activation of MMP-2 in the autopsy specimen. MIB-1 staining index and phosphorylation levels of p44/42-mitogen-activated protein kinase did not change, whereas phosphorylated protein kinase B (Akt) was decreased in the autopsy specimen, suggesting compensation and/or amplification of other proliferative signaling pathways such as suppression of apoptosis signaling. Consequently, bevacizumab might inhibit the VEGF autocrine loop, which then causes a change in molecular expression related not only to enhancement of tumor invasion but also maintenance of tumor proliferation.     

Implications of bevacizumab discontinuation in adults with recurrent glioblastoma

Background

Patients with recurrent glioblastoma benefiting from bevacizumab are often treated indefinitely due to concerns regarding rebound tumor recurrence upon discontinuation. However, treatment is discontinued for reasons other than disease progression in a subset of these patients, the characteristics and outcomes of which are poorly defined.

Methods

Of 342 adults with recurrent glioblastoma in our database treated with bevacizumab, 82 received treatment for ≥6 months; of these, bevacizumab was discontinued for reasons other than tumor progression in 18 patients (Bev-D) and for disease progression in the remainder (Bev-S). The impact of discontinuation on outcome was assessed with discontinuation as a time-dependent covariate in a Cox hazards model for progression-free survival.

Results

There was no difference in hazard rates for progression between Bev-D and Bev-S groups; the adjusted hazard ratio for progression using discontinuation as a time-dependent covariate was 0.91 (95% CI:0.47, 1.78). The median PFS after bevacizumab-discontinuation was 27 weeks (95% CI:15-NR). At progression, a higher proportion of Bev-D patients had local progression compared with the Bev-S patients. Salvage therapy in Bev-D patients yielded a PFS-26 weeks of 47% (95% CI:23%–94%) with a median PFS of 23 weeks (95% CI:12-NR), vs. 5% (95% CI: 1%–21%) and 9 weeks (95% CI: 6–11) in Bev-S patients (HR:0.3;CI, 0.1–0.6) (P = .0007).

Conclusions

Bevacizumab discontinuation unrelated to disease progression does not appear to cause rebound recurrence or worsen PFS in patients who benefit from bevacizumab. Additionally, Bev-D patients had an improved response to salvage therapy, findings which provide a strong basis for a prospective study.     

Relative cerebral blood volume is a potential predictive imaging biomarker of bevacizumab efficacy in recurrent glioblastoma

Background

To analyze the relevance of dynamic susceptibility-weighted contrast-enhanced MRI (DSC-MRI) derived relative cerebral blood volume (rCBV) analysis for predicting response to bevacizumab (BEV) in patients with recurrent glioblastoma (rGB).

Methods

A total of 127 patients diagnosed with rGB receiving either bevacizumab (71 patients, BEV cohort) or alkylating chemotherapy (56 patients, non–BEV cohort) underwent conventional anatomic MRI and DSC-MRI at baseline and at first follow-up after treatment initiation. The mean rCBV of the contrast-enhancing tumor (cT1) as well as cT1 and fluid-attenuated inversion recovery (FLAIR) volumes at both time points were correlated with progression-free survival (PFS) and overall survival (OS) using Cox proportional hazard models, logisticregression, and the log-rank test.

Results

Baseline rCBV was associated with both PFS (hazard ratio [HR] = 1.3; P < .01) and OS (HR = 1.3; P < .01) in the BEV cohort and predicted 6-month PFS in 82% and 12-month OS in 79% of patients, whereas it was not associated with PFS (HR = 1.0; P = .70) or OS (HR = 1.0; P = .47) in the non-BEV cohort. Corresponding median OS and PFS rates in the BEV cohort for patients with rCBV-values less than 3.92 (optimal threshold from receiver operating characteristic [ROC] analysis of 12-month OS data) were 14.2 and 6.0 months, as compared to 6.6 and 2.8 months for patients with rCBV-values greater than 3.92 (P < .01, respectively). cT1 and FLAIR volumes at first follow-up were significant predictors of 6-month PFS and 12-month OS in the BEV cohort but not in the non-BEVcohort. Corresponding volumes at baseline were not significant in any cohort.

Conclusions

Pretreatment rCBV is a potential predictive imaging biomarker in BEV-treated rGB but not alkylating chemotherapy-treated rGB, which is superior to volumetric analysis of conventional anatomic MRI and predicts 6-month PFS and 12-month OS in 80% of BEV-treated patients.