Bevacizumab in the treatment of ovarian cancer
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Abstract:
Current treatment for epithelial ovarian cancer involves a combination of surgery and chemotherapy with platinum- and taxane-based chemotherapy. With the recent approval of the anti-VEGF antibody bevacizumab by several regulatory bodies in colorectal and non-small-cell lung cancers, interest has developed regarding the potential role of bevacizumab therapy in ovarian cancer. Several case series and Phase II studies indicate that in ovarian cancer bevacizumab is active as a single agent or in combination with other drugs. Currently, ongoing Phase III trials are testing bevacizumab in front-line adjuvant therapy with carboplatin and paclitaxel. Bevacizumab has been generally well tolerated in ovarian cancer patients, but recent reports on increased risk of gastrointestinal perforations have gained attention. Bevacizumab offers a novel therapeutic modality in the treatment of epithelial ovarian cancers.Keywords:
Carboplatin
Taxane
First-line ovarian cancer platinum doublet is paclitaxel-carboplatin. Superiority of weekly paclitaxel schedules has not been confirmed; however, a novel schedule with both drugs given weekly (days 1, 8, 15) followed by a 2-week break may be advantageous to some.
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调查 CMNa 的效果的目的在操作以后的先进卵巢的癌症病人在提高的 CA125 层次上与 paclitaxel 和 carboplatin 结合了。CMNa 的效果在 25 个操作以后的先进卵巢的癌症病人在提高的 CA125 层次上与 paclitaxel 和 carboplatin 相结合的方法回顾地被分析并且与那些相比在 20 个控制案例中。结果在 1 化疗骑车以后， CA125 与控制，而是有的不统计的意义相比铺平有的减少的趋势。当时在化疗的二个周期以后， CA125 层次在控制与那些相比更快减少了。在二个组的副作用是相似的。与 paclitaxel 和 carboplatine 相结合的结论 CMNa 比 paclitaxel 和 carboplatin 在操作以后的先进卵巢的癌症的治疗有提高的 CA125 层次在减少中有更强壮的效果，它显示 CMNa 在 paclitaxel 和 carboplatin 的化疗上有敏化 chemo 效果。
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A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab.
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It has been reported that bevacizumab in combination with paclitaxel significantly prolongs progression-free survival compared with paclitaxel alone in the initial treatment for metastatic breast cancer. To understand how bevacizumab enhances the efficacy of paclitaxel, we investigated the mechanism in a MX-1 human breast cancer xenograft model. The antitumor activity of bevacizumab at 5 mg/kg in combination with paclitaxel at 20 or 30 mg/kg was significantly higher than that of either agent alone. First, we measured the paclitaxel concentration in tumor to see whether bevacizumab enhances the activity by increasing the tumor concentration of paclitaxel. When given in combination with bevacizumab, the levels of paclitaxel in the tumor increased. Paclitaxel at 30 mg/kg with bevacizumab showed a similar tumor concentration as paclitaxel alone at either 60 or 100 mg/kg, with a similar degree of tumor growth inhibition. In contrast, no remarkable differences in paclitaxel concentration in the plasma or liver were observed between the paclitaxel monotherapy group and the paclitaxel plus bevacizumab group. An increase in paclitaxel concentration by bevacizumab was also found in another model, A549. In the same MX-1 model, vascular permeability in the tumor was significantly decreased by treatment with bevacizumab. There was no difference in microvessel density between the bevacizumab alone group and the combination group. Results suggest that the synergistic antitumor activity of paclitaxel and bevacizumab in combination may be a result of the increase in paclitaxel concentration in tumor resulting from the downregulation of vascular permeability when co-administered with bevacizumab.
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Purpose: Retinoblastoma (Rb) is a rare childhood cancer of the retina with a survival rate of 95% in children living in high-income countries, after appropriate therapies such as chemotherapy, local ophthalmologic treatment, and radiotherapy. However, due to inactivation of the RB1 gene, all bilateral and almost 15% of unilateral retinoblastoma patients have a higher risk of s econdary cancers, especially sarcomas. Hence, new nonmutagen treatments are warranted. Therefore, we investigated the efficacy of therapy using anti-VEGF antibody bevacizumab, either alone or with carboplatin, in well-characterized Rb patient-derived xenografts (PDXs). Methods: Three Rb PDXs previously established and characterized, RB102, RB111, and RB200, have been treated using carboplatin, bevacizumab, or carboplatin + bevacizumab. In order to define antitumor responses, various quantitative PCR and histopathologic analyses have then been performed on tumors collected at the end of experiments. Results: In all treated PDX models, we have observed a high and significant improvement of chemotherapy-induced in vivo efficacy by the antiangiogenic antibody. The overall response rate, lower than −0.5, was 48%, 27%, and 86% after carboplatin, bevacizumab, and carboplatin + bevacizumab, respectively (carboplatin versus carboplatin + bevacizumab; P < 10−2; bevacizumab versus carboplatin + bevacizumab; P < 10−3). In the Rb200 PDX, such a result was also observed when bevacizumab was combined with lower doses of carboplatin. Quantitative PCR and histopathologic analyses have been performed and confirmed the impact of the bevacizumab-based treatments on various angiogenic markers. Conclusions: Overall, our in vivo results confirm the interest in antiangiogenic therapy for the treatment of Rb in combination with carboplatin and provide a robust rationale for testing this combination in the clinical setting for Rb patients.
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Purpose: To evaluate the effect of four taxane drugs, namely, paclitaxel, docetaxel, paclitaxel liposomes (Lipusu), and nab-paclitaxel (Keaili) on ovarian cancer cells both in vivo and in vitro.
Methods: BALB/c-nu/nu female mice were used to develop mouse xenograft models. The mice were randomized to 5 groups (4 in each group), namely, control (PBS) group, paclitaxel group, docetaxel group, liposomal paclitaxel group and nab-paclitaxel group. The effect of four taxane drugs were determined via cell proliferation and toxicity tests. Mouse xenograft models were employed to assess the efficacy of four taxane drugs in inhibiting tumor growth.
Results: Nab-paclitaxel has a significant ovarian growth-reducing effect in vitro. In vivo, no significant differences were observed in tumor volume among the four groups (p < 0.05). Nab-paclitaxel produced the lowest animal toxicity when compared with other three drugs as the mice in nab- paclitaxel treatment group showed no significant alterations in body weight (p < 0.05). Hematoxylin and eosin (H & E) staining revealed the lowest degree of liver tissue damage in mice treated with nab-paclitaxel compared to mice administered the other three paclitaxels.
Conclusion: Nab-paclitaxel is more effective in mice with ovarian cancer than traditional paclitaxels. Thus, it promises to offer a viable alternative as first- line chemotherapy for epithelial ovarian cancer in humans, as it has low systemic toxicity and fewer hypersensitivity reactions. However, further investigations, including clinical trials in humans, are required.
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AbstractThe combination of carboplatin and paclitaxel is widely used to treat multiple solid tumors including ovarian, lung and breast cancer. Usually these drugs are given simultaneously with little regard to the importance of scheduling to obtain a maximal response. To investigate the importance of sequencing, the human breast Bcap37 and ovarian OV2008 cancer cell lines were exposed to carboplatin and paclitaxel in three different sequences: 1) pretreatment with paclitaxel followed by carboplatin; 2) pretreatment of carboplatin followed by paclitaxel and 3) simultaneous treatment with these two agents. The combination of carboplatin and paclitaxel resulted in antagonistic interactions when tumor cells were exposed to carboplatin prior to paclitaxel or exposed to the two drugs simultaneously, but there was little antagonistic interaction observed when paclitaxel was administered before carboplatin. Biochemical examination revealed that pretreatment or cotreatment of carboplatin inhibited paclitaxel-induced IκBα degradation and bcl-2 phosphorylation. Further analyses demonstrated that carboplatin could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel was administered before carboplatin. These results indicate that the interaction between paclitaxel and carboplatin is highly schedule dependent. The optimal schedule for this combination is sequential exposure of paclitaxel followed by carboplatin.
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