Purpose
Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study ...was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib.
Methods
Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1,000 mg/m
2
on days 1 and 8), cisplatin (70 mg/m
2
), or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1–5, 8–12, and 15–19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3 + 3 dose escalation rules.
Results
Fourteen patients with advanced solid tumors were enrolled, five to the cisplatin arm and nine to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of two cycles of treatment (range 1–5), and patients enrolled in the carboplatin arm received a median of one cycle of treatment (range 1–4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia), and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort, and the study was closed. No patients achieved an objective response to treatment.
Conclusions
Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression.
Primary leiomyosarcomas of the inferior vena cava (IVC) are rare tumors associated with poor prognosis, and surgical resection with the goal of obtaining negative margins is the gold standard for ...initial treatment. Tumor characteristics of both extraluminal extension into renal parenchyma and intraluminal extension of the subdiaphragmatic IVC are even less common. The prognosis of vascular leiomyosarcomas is determined by the location and the size of the tumor, as these factors determine the risk of local recurrence and metastasis. We present a case of a 30-year old female incidentally found to have a 14 cm right renal mass and IVC thrombus.
Micro-Abstract Combination cisplatin-based chemotherapy is indicated for patients with advanced bladder cancer, but use is often limited due to renal insufficiency. In this study, we retrospectively ...evaluated the renal function in patients with urothelial cancer by using 2 formulas and determined that the Chronic Kidney Disease Epidemiology Collaboration formula is less likely to deem a patient ineligible for cisplatin-based therapy compared with the Cockroft-Gault formula by using standard renal function thresholds. This finding warrants further prospective evaluation.
Purpose
The incidental detection of early-stage kidney tumors is increasing in the United States. Nephron-sparing approaches (NS) to managing these tumors are equivalent to radical nephrectomy (RN) ...in oncologic outcomes and have a decreased impact on renal function. Our objective was to evaluate trends in the use of NS over the past decade and the socioeconomic factors associated with its use.
Methods
The National Cancer Database was queried to identify patients with stage I kidney cancer between 2000 and 2008. Patients were classified by the type of surgery as NS (local destruction and local excision) or RN. Patients were further categorized by age, race, insurance status, and income. Log-binomial regression was used to estimate prevalence ratios (PR) for the proportion of NS to RN according to demographic and socioeconomic characteristics.
Results
From 2000 to 2008, there were 142,194 cases of kidney cancer reported to the NCDB. In these cases, 43,034 (30.3 %) patients had NS, and 86,431 (60.78 %) patients had RN. The prevalence of NS increased 10 % per year (PR = 1.10,
p
< 0.0001)—from 20.0 % in 2000 to 45.1 % in 2008. Older age, lower income, Black race, Hispanic ethnicity, and lack of health insurance were associated with a decreased prevalence of NS.
Conclusions
NS as a treatment for stage I kidney cancer has increased steadily since 2000. Age, racial, and socioeconomic differences may exist in the utilization of NS. Additional analyses, with patient level data, are required to address the independent significance of these variables in an effort to develop strategies to mitigate these potential disparities.
Targeted molecular therapy has been an elusive goal in the treatment of neo-plastic diseases. While chemotherapy has improved the outcome of many cancers, a non-selective cytotoxic approach ...invariably causes damage to normal cells, resulting in side effects and limiting treatment efficacy. This is evident in the evolution of treatment for castration-resistant prostate cancer （CRPC）. For instance, while mitoxantrone,
Introduction:
Despite increasing early detection and treatment of prostate cancer, a subset of patients presents with or develops metastatic disease. Androgen deprivation therapy is effective but ...resistance eventually develops, resulting in a lethal phenotype known as castration-resistant prostate cancer (CRPC). Recently, several novel treatments, each with distinct mechanisms of actions, have been approved for the treatment of CRPC. Understanding of the metabolic and toxicological considerations of each treatment is crucial to the successful management of patients with this lethal disease.
Areas covered:
The present review focuses on the metabolism and toxicology characteristics of recently approved therapies in the treatment of metastatic CRPC. Specifically, the authors review the mechanism of action of these therapies in addition to their, efficacy and usage recommendations for hepatic and renal impairment. The authors, furthermore, also consider their adverse effect profile.
Expert opinion:
Despite the expanding armamentarium of effective treatments for CRPC, the exact choice, timing and sequence of various therapies remains an inexact science and requires further investigation. Variations in patient comorbidities, disease burden, organ functions and adverse events are all critical determinants in selection of treatment. Identification and validation of molecular pathways and specific targets that drives disease progression will be critical in the continued development of effective treatments in advanced prostate cancer.
PURPOSE OF REVIEWRecent advances in our understanding of the androgen axis signaling pathway have led to the development of therapeutic strategies to overcome the state of ‘castration resistance’ in ...prostate cancer. In this review, we examine the mechanisms of castration resistance, as well as recently reported and ongoing clinical studies, which will further identify therapeutic opportunities for novel therapeutics targeting the androgen-signaling axis in advanced prostate cancer.
RECENT FINDINGSAs evidenced by recently reported positive phase III clinical trials, secondary hormonal agents such as abiraterone and MDV3100 may still be very effective in the treatment of castration-resistant prostate cancer, even after the use of docetaxel chemotherapy.
SUMMARYNovel agents targeting this pathway have demonstrated a proof of principle that overcoming castration resistance is possible, leading to significant changes in the landscape of treatment in this disease. The optimal combination, sequence, and pattern of use in these novel therapies will be the focus of clinical research in the near future.
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