Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary peritoneal/fallopian tube cancers: A retrospective review
“…Weekly administered ixabepilone was retrospectively evaluated with or without bevacizumab for 24 uterine and 36 ovarian, primary peritoneal and fallopian tube cancers. For uterine cancers, addition of bevacizumab significantly increased both PFS (3.0 months versus 6.5 months) and OS (4.2 months versus 9.6 months); it was reported that similar results were estimated for ovarian cancer [149]. A meta-analysis evaluating the role of bevacizumab concluded that there is an advantage of PFS and OS when chemotherapy was combined with bevacizumab and increased risk of non-CNS bleeding, hypertension, gastrointestinal perforation, thromboembolism, and proteinuria [150].…”
Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts’ immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.
“…Weekly administered ixabepilone was retrospectively evaluated with or without bevacizumab for 24 uterine and 36 ovarian, primary peritoneal and fallopian tube cancers. For uterine cancers, addition of bevacizumab significantly increased both PFS (3.0 months versus 6.5 months) and OS (4.2 months versus 9.6 months); it was reported that similar results were estimated for ovarian cancer [149]. A meta-analysis evaluating the role of bevacizumab concluded that there is an advantage of PFS and OS when chemotherapy was combined with bevacizumab and increased risk of non-CNS bleeding, hypertension, gastrointestinal perforation, thromboembolism, and proteinuria [150].…”
Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts’ immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.
“…Preclinical data from several in vivo models including breast, kidney, lung, and colon cancers demonstrated increased activity of ixabepilone in combination with bevacizumab, suggesting a synergistic effect in both antitumor and antiangiogenic activities and the absence of overlapping toxicities . More recently, randomized trials reported acceptable activities and toxicities of combined therapy in platinum/taxane‐resistant cervical‐uterine and locally recurrent or metastatic breast cancer . …”
Lessons Learned.
Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression‐free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development.Background.Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule‐stabilizing agent approved for the treatment of breast cancer, is active in taxane‐sensitive and ‐resistant cells. In this single‐arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC.Methods.We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)‐approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression‐free survival (PFS), overall survival (OS), and the toxicity of the combination.Results.The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2–54). The median follow‐up was 36.4 months (range 23.5–96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9–10.6) and the median OS was 15.0 months (95% CI, 11.3–28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%).Conclusion.The combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second ‐ or later‐line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.
“…Ixabepilone has been shown to have inhibitory concentrations of 50% (IC 50 s) an order of magnitude lower than typical concentrations seen with paclitaxel, and also has less neuropathies and other side effects in patients [ 62 ]. Positive clinical outcomes have been seen using Ixabepilone in recurrent ovarian cancer in combination with bevacizumab, and studies are ongoing to determine optimum patient enrollment criteria [ 66 ]. These results may highlight the utility of combination therapies that are not directly targeting major mechanisms of chemoresistance in ovarian cancer [ 35 ].…”
Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. One of the leading causes of death in high-grade serous ovarian cancer (HGSOC) is chemoresistant disease, which may present as intrinsic or acquired resistance to therapies. Here we discuss some of the known molecular mechanisms of chemoresistance that have been exhaustively investigated in chemoresistant ovarian cancer, including drug efflux pump multidrug resistance protein 1 (MDR1), the epithelial–mesenchymal transition, DNA damage and repair capacity. We also discuss novel therapeutics that may address some of the challenges in bringing approaches that target chemoresistant processes from bench to bedside. Some of these new therapies include novel drug delivery systems, targets that may halt adaptive changes in the tumor, exploitation of tumor mutations that leave cancer cells vulnerable to irreversible damage, and novel drugs that target ribosomal biogenesis, a process that may be uniquely different in cancer versus non-cancerous cells. Each of these approaches, or a combination of them, may provide a greater number of positive outcomes for a broader population of HGSOC patients.
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