Unit of Medical Oncology 2, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Clin Cancer Res. 2010 Dec 1;16(23):5862-72. doi: 10.1158/1078-0432.CCR-10-2363. Epub 2010 Oct 28.
To assess the clinical and biological activity of the association of bevacizumab and fotemustine as first-line treatment in advanced melanoma patients.
Previously untreated, metastatic melanoma patients (n = 20) received bevacizumab (at 15 mg/kg every 3 weeks) and fotemustine (100 mg/m² by intravenous administration on days 1, 8, and 15, repeated after 4 weeks) in a multicenter, single-arm, open-label, phase II study. Primary endpoint was the best overall response rate; other endpoints were toxicity, time to progression (TTP), and overall survival (OS). Serum cytokines, angiogenesis, and lymphangiogenesis factors were monitored by multiplex arrays and by in vitro angiogenesis assays. Effects of fotemustine on melanoma cells, in vitro, on vascular endothelial growth factor (VEGF)-C release and apoptosis were assessed by ELISA and flow cytometry, respectively.
One complete response, 2 partial responses (PR), and 10 patients with stable disease were observed. TTP and OS were 8.3 and 20.5 months, respectively. Fourteen patients experienced adverse events of toxicity grade 3-4. Serum VEGF-A levels in evaluated patients (n = 15) and overall serum proangiogenic activity were significantly inhibited. A significant reduction in VEGF-C levels was found in several post-versus pretherapy serum samples. In vitro, fotemustine inhibited VEGF-C release by melanoma cells without inducing significant cell death. Serum levels of interleukin (IL)-10 and IL-12p70 showed the highest levels in sera of PR patients, compared with patients with stable or progressive disease whereas IL-23 showed the opposite pattern.
The combination of bevacizumab plus fotemustine has clinical activity in advanced melanoma and promotes systemic modulation of angiogenesis and lymphangiogenesis factors.
评估贝伐珠单抗联合福莫司汀作为晚期黑色素瘤患者一线治疗的临床和生物学活性。
在这项多中心、单臂、开放标签、Ⅱ期研究中，先前未经治疗的转移性黑色素瘤患者（n=20）接受贝伐珠单抗（每 3 周 15mg/kg）和福莫司汀（静脉注射 100mg/m²，第 1、8 和 15 天，4 周后重复）治疗。主要终点是最佳总体缓解率；其他终点是毒性、无进展生存期（TTP）和总生存期（OS）。通过多重分析和体外血管生成测定，监测血清细胞因子、血管生成和淋巴管生成因子。通过 ELISA 和流式细胞术分别评估福莫司汀对黑色素瘤细胞、血管内皮生长因子（VEGF）-C 释放和细胞凋亡的体外作用。
观察到 1 例完全缓解、2 例部分缓解（PR）和 10 例疾病稳定的患者。TTP 和 OS 分别为 8.3 个月和 20.5 个月。14 例患者发生 3-4 级毒性事件。在评估的患者（n=15）和总体血清促血管生成活性中，血清 VEGF-A 水平显著受到抑制。在几个治疗前后的血清样本中发现 VEGF-C 水平显著降低。体外，福莫司汀抑制黑色素瘤细胞释放 VEGF-C，而不诱导明显的细胞死亡。PR 患者的血清白细胞介素（IL）-10 和 IL-12p70 水平最高，与稳定或进展性疾病患者相比，而 IL-23 则呈现相反的模式。
贝伐珠单抗联合福莫司汀在晚期黑色素瘤中有临床活性，并促进血管生成和淋巴管生成因子的全身调节。
