Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab
Ryota TamuraToshihide TanakaKentaro OharaKeisuke MiyakeYukina MorimotoYohei YamamotoRyuichi KanaiYasuharu AkasakiYuichi MurayamaTakashi TamiyaKazunari YoshidaHikaru Sasaki
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Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post-Bev recurrent tumors from 9 patients were included. The expression of programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD-L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The PD-1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post-Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long-term Bev therapy.Group B
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Bevacizumab使用中の手術は創傷治癒遅延のため投与後4∼6週間以降に施行することが推奨されているが，消化管穿孔などでは緊急手術が必要となる．今回，Bevacizumab使用中に緊急手術行った2例を報告する．症例1,50歳代男性.下行結腸癌同時性肝転移肺転移と診断され，腫瘍によるイレウスに対して人工肛門造設術を施行，その後，腫瘍の後腹膜への穿通に対して結腸左半切除術を施行．8日後に腸腰筋膿瘍に対して洗浄ドレナージ術を施行．症例2,70歳代男性.虫垂粘液嚢胞腺癌,腹膜播種と診断され治療を行っていた．消化管穿孔に対して緊急手術を施行．横行結腸に穿孔部が認められたが高度の癌性腹膜炎の状態であり洗浄ドレナージ術を施行し治療した．Bevacizumab使用時において消化管吻合が可能な場合においても吻合を行わず，人工肛門造設による2期的手術を行い，人工肛門閉鎖については，十分なBevacizumab休薬期間と原疾患の進行状況に合わせてその時期を検討する必要がある．
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Bevacizumab is a humanized monoclonal antibody to VEGF, and the incorporation of bevacizumab to chemotherapy is one of the rapidly evolving areas in the treatment of breast cancer. Bevacizumab in combination with chemotherapy versus chemotherapy alone improves progression-free survival and increases the response rate in first-line therapy for locally recurrent or metastatic breast cancer. This approach has been and is still being evaluated for early breast cancer in neoadjuvant and adjuvant settings. Bevacizumab is well tolerated and has an established tolerability profile. Both tumor- and host-related biomarkers of bevacizumab activity, response and benefit are emerging from Phase I, II and III clinical trials. The biomarkers of benefit will ultimately help identify the subgroups of patients who specifically benefit from anti-VEGF therapy with bevacizumab.
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Colorectal cancer is one of the most common cancers worldwide. The prognosis of patients with metastatic colorectal cancer in recent years has increased from 5 months with best supportive care to nearly 2 years with chemotherapy combined with bevacizumab, an antivascular endothelial growth factor monoclonal antibody. New prognostic and predictive biomarkers have been identified to guide chemotherapy in metastatic colorectal cancer, such as KRAS and BRAF oncogenes. However, the status of these oncogenes does not affect the efficacy of bevacizumab, and biomarkers predicting response to treatment with bevacizumab are still lacking. Addition of bevacizumab to regimens based on fluoropyrimidines or irinotecan has been shown to improve overall survival in treatment-naïve patients with metastatic colorectal cancer. Similarly, a significant increase in overall survival rate is achieved by adding bevacizumab to fluoropyrimidines and oxaliplatin in patients with disease progression. Bevacizumab has been found to be effective even when used as third-line therapy and later. In addition, cohort studies have shown that bevacizumab improves survival significantly despite disease progression. Finally, bevacizumab therapy in the neoadjuvant setting for the treatment of liver metastasis is well tolerated, safe, and effective.
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有 bevacizumab 的治疗，一个 antiangiogenic 代理人，在病人与变形或 unresectable colorectal 癌症不到 4 年以前在日本被同意。Bevacizumab 与变形 colorectal 癌症改进病人的幸存；然而，它可以导致象流血那样的复杂并发症，它有时是致命的。因为治疗的潜在的风险超过它的好处， Bevacizumab 应该仅仅在小心的考虑以后被管理。因此，药品的公司不与大脑转移为病人推荐 bevacizumab 治疗。当一些报告支持 bevacizumab 的小心的使用时，其它报导与转移在病人禁止它的使用到中央神经系统(CNS ) 不总是是必要的，包括大脑。因此，在有大脑转移的 colorectal 癌症病人的 bevacizumab 治疗是争论的，并且大脑转移是否在反脉管的 endothelial 生长期间是为 intracranial 出血的一个风险因素，是不清楚的因素(VEGF ) 治疗。没有大脑转移，我们与周期性的 colorectal 癌症报导一个 65 岁的人和一个 65 岁的人；分别地，这些病人在 bevacizumab 的管理以后开发了 multifocal 和独居的 intracranial 出血。我们的调查结果建议就算病人没在 bevacizumab 治疗以前有大脑转移并且也建议大脑转移不是为有 bevacizumab 治疗的 intracranial 出血的一个风险因素，那 intracranial 出血能发生。这些调查结果也询问在 anti-VEGF 上从临床的试用与大脑转移排除病人的必要性治疗。
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The use of bevacizumab in combination with fluoropyrimidine-containing chemotherapy is a well-established first-line and second-line treatment for patients with metastatic colorectal cancer (mCRC). However, there remains a need for reproducible, validated, inexpensive and accessible prognostic markers to aid treatment selection. The optimal treatment duration and the role of bevacizumab in certain patient subgroups, considered at particular risk of bevacizumab-mediated toxicity, also require further investigation. The aim of the ASCENT study [an Australian translational Study to evaluate the prognostic role of inflammatory markers in patients with metastatic ColorEctal caNcer Treated with bevacizumab (Avastin™)] is to evaluate the relationship between the host inflammatory response as measured by neutrophil/lymphocyte ratio (NLR) and treatment outcomes in patients with previously untreated mCRC receiving bevacizumab-based first- and second-line treatment. This open-label, prospective, single arm, phase IV, Australian multi-centre study evaluates the relationship between the host inflammatory response as measured by NLR and treatment outcomes in patients with previously untreated mCRC receiving bevacizumab-based first- and second-line treatment. 150 patients will be recruited from 16 centres around Australia. Patients will receive trial treatments in two phases: Phase A: XELOX or mFOLFOX6 plus bevacizumab administered from study start until first disease progression; and Phase B: FOLFIRI plus bevacizumab administered from first disease progression until second disease progression. The primary analysis will test the association between NLR and progression free survival using a proportional Hazards Model. Secondary analyses will investigate whether the relationship can be improved upon with other prognostic biomarkers, and further characterise the safety of bevacizumab following treatment initiation, and when continued after progression in combination with standard chemotherapy regimens (presented through summary statistics and Kaplan Meier curves). Quantifying the relationship between NLR and PFS will inform decision making on the extent to which this simple metric may be applied clinically. ClinicalTrials.gov: NCT01588990
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症例 1：75 歳，女性。左肺癌術後再発，多発骨転移に対して docetaxel，bevacizumab 併用化学療法が開始された。投与 2 カ月後に食欲低下，発熱性好中球減少症を認め一旦休薬となった。3 カ月間休薬し，再投与 2 カ月後に右足首に潰瘍が出現したため当科へ紹介され受診した。当科受診時 bevacizumab は休薬されており，保存的治療で右足背の潰瘍は縮小傾向を認めていたが，その後 bevacizumab の投与が再開され急速に既存の潰瘍が拡大した。症例 2：62 歳，女性。再発乳癌，骨，肝転移に対して paclitaxel，bevacizumab 併用化学療法が開始された。投与 3 カ月後に右足背に潰瘍が出現し当科へ紹介され受診した。2 症例とも血液検査，画像検査で特に有意な所見は認められなかった。病理組織学的に表皮壊死，好中球を含む炎症細胞浸潤，毛細血管の増生とフィブリノイド変性，出血像を認めた。検査結果，臨床経過から bevacizumab による潰瘍と診断した。2 症例とも bevacizumab の投与を中止し，保存的潰瘍治療を行った。症例 1 では潰瘍はほとんど改善がみられず，全身状態が徐々に悪化し，再々投与 3 カ月後に原病死した。症例 2 は bevacizumab の投与中止後 8 カ月経過した時点で良好な肉芽組織の増生を認めている。 皮膚潰瘍を診察した際には，bevacizumab によるものも念頭に置き，投与中止など適切に対応する必要がある。
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Manifold data have demonstrated that the addition of bevacizumab to chemotherapy improved progression-free survival (PFS), while few trials have revealed its significant overall survival (OS) benefit. Furthermore, it still remains suspended how to maximize the benefits of bevacizumab as first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer. We sought to conduct a meta-analysis to assess the benefits of bevacizumab with chemotherapy and to identify the ideal chemotherapy partner of bevacizumab in the first-line setting for HER2-negative advanced breast cancer patients.Computerized and manual searches were performed to identify randomized clinical trials evaluating the efficacy of bevacizumab plus chemotherapy versus chemotherapy alone or bevacizumab with different chemotherapy regimens as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer patients. Risk ratios or odds ratios with their 95% CIs were used to estimate the association between multiple combinations of bevacizumab with chemotherapy and various clinical outcomes.With 7 trials identified, this analysis included 3,984 eligible patients. The addition of bevacizumab to chemotherapy resulted in a statistically significant improvement in PFS (P=0.019) and objective response rate (ORR; P<0.001) rather than in OS (P=0.783) when compared with chemotherapy alone. The greater benefits in PFS and ORR were achieved from bevacizumab plus taxane-based regimens compared with bevacizumab plus capecitabine-based regimens, while bevacizumab plus capecitabine had comparable OS with bevacizumab plus paclitaxel. Additionally, bevacizumab-based triplet therapy failed to improve the clinical outcomes when compared with doublet therapy.This meta-analysis reveals that the addition of bevacizumab to chemotherapy yielded PFS and ORR benefits in HER2-negative advanced breast cancer. Additional studies are still prompted to further optimize the first-line treatment of bevacizumab.
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