Targeted antiangiogenic agents in combination with cytotoxic chemotherapy in preclinical and clinical studies in sarcoma

Sarcomas are a heterogeneous group of mesenchymal malignancies. In recent years, studies have demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of sarcomas. However, when used as monotherapy in the clinical setting, these targeted antiangiogenic agents have only provided modest survival benefits in some sarcoma subtypes, and have not been efficacious in others. Preclinical and early clinical data suggest that the addition of conventional chemotherapy to antiangiogenic agents may lead to more effective therapies for patients with these tumors. In the current review, the authors summarize the available evidence and possible mechanisms supporting this approach

Pharmacokinetics and Pharmacogenetics of Metronomic Chemotherapy

Despite the numerous preclinical and clinical studies that have been conducted on metronomic chemotherapy in the past 10 years, few pharmacokinetic and pharmacogenetics data on this dosing regimen are available. Indeed, only the pharmacokinetics of metronomically administered drugs, such as irinotecan, UFT, and vinorelbine, have been described in patients, but no data are available on the most widely explored agents in such an approach like cyclophosphamide or capecitabine. Methodological issues and the neglected importance of the relationship between plasma concentrations of metronomically administered chemotherapeutic drugs (and their active metabolites) contributed to the absence of data on the commonly used 50 mg/day cyclophosphamide schedule. Moreover, few data are available on the pharmacogenetics of metronomic chemotherapy, and, although some objective responses have been obtained in various tumors, it remains largely unknown which genetic backgrounds could affect or predict the clinical response of patients. Trials integrating pharmacokinetic and pharmacogenetics research are necessary to better evaluate the clinical benefit of metronomic chemotherapy

Pharmacokinetics and pharmacogenetics of metronomic chemotherapy.

Despite the numerous preclinical and clinical studies that have been conducted on metronomic chemotherapy in the past 10 years, few pharmacokinetic and pharmacogenetics data on this dosing regimen are available. Indeed, only the pharmacokinetics of metronomically administered drugs, such as irinotecan, UFT, and vinorelbine, have been described in patients, but no data are available on the most widely explored agents in such an approach like cyclophosphamide or capecitabine. Methodological issues and the neglected importance of the relationship between plasma concentrations of metronomically administered chemotherapeutic drugs (and their active metabolites) contributed to the absence of data on the commonly used 50 mg/day cyclophosphamide schedule. Moreover, few data are available on the pharmacogenetics of metronomic chemotherapy, and, although some objective responses have been obtained in various tumors, it remains largely unknown which genetic backgrounds could affect or predict the clinical response of patients. Trials integrating pharmacokinetic and pharmacogenetics research are necessary to better evaluate the clinical benefit of metronomic chemotherapy

Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect

Metronomic chemotherapy describes the close, regular administration of chemotherapy drugs at less-toxic doses over prolonged periods of time. In 2015, the results of randomized phase III clinical trials demonstrated encouraging, albeit limited, efficacy benefits of metronomic chemotherapy regimens administered as adjuvant maintenance therapy for the treatment of breast cancer, or as maintenance therapy in combination with an antiangiogenic agent for metastatic colorectal cancer. Owing to the investigational nature of this approach, metronomic chemotherapy regimens are highly empirical in terms of the optimal dose and schedule for the drugs administered; therefore, greater knowledge of the pharmacokinetics of metronomic chemotherapy is critical to the future success of this treatment strategy. Unfortunately, such preclinical and clinical pharmacokinetic studies are rare. Herein, we present situations in which active drug concentrations have been achieved with metronomic schedules, and discuss their associated pharmacokinetic parameters. We summarize examples from the limited number of clinical studies in order to illustrate the importance of assessing such pharmacokinetic parameters, and discuss the influence this information can have on improving efficacy and reducing toxicity