Clinical Outcome of Cytoreductive Surgery Prior to Bevacizumab for Patients with Recurrent Glioblastoma: A Single-center Retrospective Analysis

Bevacizumab (BEV) is a key anti-angiogenic agent used in the treatment for recurrent glioblastoma multiforme (GBM). The aim of this study was to investigate whether cytoreductive surgery prior to treatment with BEV contributes to prolongation of survival for patients with recurrent GBM. We retrospectively analyzed the treatment outcomes of 124 patients with recurrent GBM who were initially treated with the Stupp protocol between 2006 and 2019. Given that BEV has only been available in Japan since 2013, we grouped the patients into two groups according to the time of first recurrence: the pre-BEV group (N = 51) included patients who had recurrence before BEV approval, and the BEV group (N = 73) included patients with recurrence after BEV approval. The overall survival after first recurrence (OS-R) was analyzed according to the treatment strategy. Among 124 patients, 27 patients (19.4%) received cytoreductive surgery. There were nine cases in the pre-BEV group and 18 cases in the BEV group. Although the mean extent of resection for both groups was almost equal, OS-R was significantly different. The median OS-R was 8.1 m in the pre-BEV group and 16.3 m in the BEV group (P = 0.007). Multivariate analysis revealed that the unavailability of BEV postoperatively (P = 0.03) and decreasing performance status by surgery (P = 0.01) were significant poor prognostic factors for survival after surgery. With the advent of BEV, cytoreductive surgery might provide superior survival benefit at the time of GBM recurrence, especially in cases where surgery can be performed without deteriorating the patient’s condition.     

Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway

Bevacizumab (Bv) can be used synergistically with fluoropyrimidine‐based chemotherapy to treat colorectal cancer. Whether and how it affects the delivery of fluoropyrimidine drugs is unknown. The present study aimed to explore the effect of Bv on the delivery of 5‐fluorouracil (5‐FU) to tumors and the underlying mechanism from metabolic perspective. Bv enhanced the anti‐tumor effects of 5‐FU in LoVo colon cancer xenograft mice and increased the 5‐FU concentration in tumors without affecting hepatic 5‐FU metabolism. Interestingly, Bv remarkably upregulated thymidine phosphorylase (TP) in tumors, which mediated the metabolic activation of 5‐FU. Although TP is reported to promote angiogenesis and resistance, the combination of Bv and 5‐FU resulted in anti‐angiogenesis and vessel normalization in tumors, indicating that the elevated TP mainly contributed to the enhanced response to 5‐FU. Bv also induced TP upregulation in LoVo cancer cells. Treatment with vascular endothelial growth factor receptor 2 (VEGFR2) antagonist apatinib and VEGFR2 silencing further confirmed TP upregulation. Bv and apatinib both enhanced the cytotoxicity of 5‐FU in LoVo cells, but there was no synergism with adriamycin and paclitaxel. We further demonstrated that the effect of Bv was dependent on VEGFR2 blockade and specificity protein 1 activation via MDM2 inhibition. In summary, Bv enhanced the accumulation of 5‐FU in tumors and the cytotoxicity of 5‐FU via TP upregulation. We provide data to better understand how Bv synergizes with 5‐FU from metabolic perspective, and it may give clues to the superiority of Bv in combination with fluoropyrimidine drugs compared to other chemotherapeutic drugs in colon cancer.     

Bevacizumab in combination with different platinum‐based doublets in the first‐line treatment for advanced nonsquamous non‐small‐cell lung cancer: A network meta‐analysis

Platinum‐based doublet chemotherapy with or without bevacizumab is the standard treatment for untreated advanced nonsquamous non‐small‐cell lung cancer (NS‐NSCLC). However, adding bevacizumab to chemotherapies other than paclitaxel–carboplatin is, though widely applied clinically, largely unjustified due to the lack of head‐to‐head data. We performed a Bayesian network meta‐analysis (NMA) to address this important issue. Data of 8,548 patients from 18 randomized controlled trials (RCTs) receiving six treatments, including taxane–platinum (Taxane–Pt), gemcitabine–platinum (Gem–Pt), pemetrexed–platinum (Pem–Pt), taxane–platinum + bevacizumab (Taxane–Pt + B), gemcitabine–platinum + bevacizumab (Gem–Pt + B) and pemetrexed–platinum + bevacizumab (Pem–Pt + B), were incorporated into the analyses. Direct and indirect evidence of overall survival (OS) and progression‐free survival (PFS) were synthesized at the hazard ratio (HR) scale and evidence of objective response rate (ORR) and serious adverse events (SAE) were synthesized at the odds ratio (OR) scale. Taxane–Pt + B showed significant advantages in OS (HR = 0.79, p < 0.001), PFS (HR = 0.54, p < 0.001) and ORR (OR = 2.7, p < 0.001) over Taxane–Pt with comparable tolerability (OR = 3.1, p = 0.08). Gem–Pt + B showed no OS benefit compared to any other treatment. No significant differences were detected between Pem–Pt + B and Pem–Pt in four outcomes. In terms of the benefit‐risk ratio, Pem–Pt and Taxane–Pt + B were ranked the first and second, respectively. In conclusion, in the first‐line treatment for advanced NS‐NSCLC, Taxane–Pt and Gem–Pt are the most and least preferable regimens to be used with bevacizumab, respectively. Adding bevacizumab to Pem–Pt remains unjustified because it fails to improve efficacy or tolerability. In terms of the benefit‐risk ratio, Pem–Pt and Taxane–Pt + B are the best and second‐best treatment for this population.     

厄洛替尼联合贝伐珠单抗治疗EGFR突变晚期非小细胞肺癌患者的有效性和安全性的Meta分析

目的：系统评价未经化疗的新确诊或复发的EGFR突变晚期非小细胞肺癌患者使用厄洛替尼或联合贝伐珠单抗治疗的有效性和安全性。方法：检索PubMed及其他数据库中截至2020年10月24日所有相关的随机对照临床试验。结果：最终纳入3项符合条件的随机对照临床研究,共计464例患者。Meta分析结果显示,厄洛替尼联合贝伐珠单抗化疗显著延长了未经化疗的新确诊或复发EGFR突变晚期非小细胞肺癌患者的无进展生存期（P<0.000 1,HR=0.62,95% CI：0.49~0.78）。然而,联合化疗并没有明显改善该患者人群的客观缓解率（P=0.19,RR=1.08,95% CI：0.96~1.22）。联合化疗组中3级及以上级别的不良事件发生率明显高于对照组（P<0.000 01,RR=1.89,95% CI：1.62~2.19）。结论：厄洛替尼联合贝伐珠单抗治疗可能会显著延长未经化疗的新确诊或复发的EGFR突变晚期非小细胞肺癌患者群体的无进展生存期,但是无法显著提高客观缓解率。同时,联合治疗方式可能会增加3级及以上不良反应的发生。这些发现可能需要更多相关临床研究进行验证。     

A case report of locally advanced triple negative breast cancer showing pathological complete response to weekly paclitaxel with bevacizumab treatment following disease progression during anthracycline-based neoadjuvant chemotherapy

IntroductionNeoadjuvant chemotherapy (NAC) is the standard of care for locally advanced triple negative breast cancer, however, approximately 5% of cases show disease progression during NAC. Although downstaging is essential to create an opportunity for curative surgery and to improve the local control outcome in such a case, no additional line of chemotherapy has been established.Case presentationA 60-year-old woman was referred to our hospital for an axillary mass presenting three weeks ago and was diagnosed as having right locally advanced (T2N2M0, stage IIIA) triple negative breast cancer. After two courses of epirubicine and cyclophosphamide as NAC, disease progression was recognized and curative resection was considered impossible due to enlarged axillary lymph nodes showing invasion to surrounding tissue. As second-line chemotherapy, weekly paclitaxel with bevacizumab treatment was initiated and significant shrinkage was immediately obtained. A clinically complete response was diagnosed after four courses of weekly paclitaxel with bevacizumab and she underwent a right breast mastectomy with axillary lymph node dissection without major complications. Histopathological examination of surgical specimens showed no residual invasive or noninvasive disease and she was diagnosed as having a pathological complete response.ConclusionsAlthough the addition of bevacizumab to standard adjuvant chemotherapy is not recommended in unselected triple negative breast cancer, the potent effect on tumor shrinkage should be considered in the treatment of locally advanced triple negative breast cancer showing disease progression during standard NAC.