1.
Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a gynecologic oncology group trial.
Matei, D, Sill, MW, Lankes, HA, DeGeest, K, Bristow, RE, Mutch, D, Yamada, SD, Cohn, D, Calvert, V, Farley, J, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;(1):69-75
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Abstract
PURPOSE Sorafenib is a kinase inhibitor targeting Raf and other kinases (ie, vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Flt3, and c-KIT). This study assessed its activity and tolerability in patients with recurrent ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC). METHODS This open-label, multi-institutional, phase II study used a two-stage design. Eligible patients had persistent or recurrent OC/PPC after one to two prior cytotoxic regimens, and they experienced progression within 12 months of platinum-based therapy. Treatment consisted of sorafenib 400 mg orally twice per day. Primary end points were progression-free survival (PFS) at 6 months and toxicity by National Cancer Institute criteria. Secondary end points were tumor response and duration of PFS and overall survival. Biomarker analyses included measurement of ERK and b-Raf expression in tumors and phosphorylation of ERK (pERK) in peripheral-blood lymphocytes (PBLs) before and after 1 month of treatment. Results Seventy-three patients were enrolled, of which 71 were eligible. Fifty-nine eligible patients (83%) had measurable disease, and 12 (17%) had detectable disease. Significant grade 3 or 4 toxicities included the following: rash (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary (n = 2). Only patients with measurable disease were used to assess efficacy. Fourteen survived progression free for at least 6 months (24%; 90% CI, 15% to 35%). Two patients had partial responses (3.4%; 90% CI, 1% to 10%); 20 had stable disease; 30 had progressive disease; and seven could not have their tumor assessed. ERK and b-Raf were expressed in all tumors. Exploratory analyses indicated that pERK in post-treatment PBL specimens was associated with PFS. CONCLUSION Sorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.
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Gitelman-like syndrome after cisplatin therapy: a case report and literature review.
Panichpisal, K, Angulo-Pernett, F, Selhi, S, Nugent, KM
BMC nephrology. 2006;:10
Abstract
BACKGROUND Cisplatin is a well-known nephrotoxic antineoplastic drug. Chronic hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria is one of the rare complications associated with its use. CASE PRESENTATION A 42-year-old woman presented with a 20 year-history of hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria after cisplatin-based chemotherapy for ovarian cancer. This patient has had chronic muscle aches and fatigue and has had episodic seizure-like activity and periodic paralysis. Only thirteen other patients with similar electrolyte abnormalities have been described in the literature. This case has the longest follow-up. CONCLUSION Cisplatin can cause permanent nephrotoxicity, including Gitelman-like syndrome. This drug should be considered among the possible causes of chronic unexplained electrolyte disorders.
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Risks and benefits of taxanes in breast and ovarian cancer.
Michaud, LB, Valero, V, Hortobagyi, G
Drug safety. 2000;(5):401-28
Abstract
The taxanes are a unique class of agents with a broad spectrum of clinical activity. They act by binding to tubulin, producing unnaturally stable microtubules and subsequent cell death. The distribution and elimination of paclitaxel depend on dose and administration rate. This nonlinearity is much less evident at lower infusion rates (24-hour infusions) and more evident at high plasma concentrations (3-hour infusions). The pharmacokinetics of docetaxel also suggest the presence of nonlinear pathways, but these appear to be clinically insignificant at the current doses utilised (60 to 100 mg/m2). Both agents undergo hepatic metabolism and biliary excretion and require dose adjustment in the setting of liver dysfunction. Drug interactions are quite common with these agents, some of which are sequence-dependent and clinically significant. The optimal dose of paclitaxel is not known at this time, and controversy over possible dose- or schedule-related differences in efficacy still remain. Docetaxel is somewhat more consistent in its dose and scheduling information, but controversy remains regarding a dose-benefit relationship as well as scheduling differences (weekly vs every 3 weeks). Toxicity profiles for these agents are somewhat different. Paclitaxel is more likely to be associated with peripheral neuropathy and myalgias/arthralgias than docetaxel. Docetaxel is more likely to be associated with a cumulative fluid retention syndrome that can be dose limiting. Paclitaxel and docetaxel are both highly active agents against breast cancer, including tumours that are resistant to anthracyclines. Docetaxel tends to have higher response rates overall, but direct comparisons at maximally tolerated doses have not been completed. Combination regimens with many different agents are attempting to improve on the responses seen with single-agent taxanes. The combination of paclitaxel and a platinum compound should be utilised as first-line therapy of advanced ovarian cancer. Controversy lies in the choice of the platinum compound and the dose and administration schedule of paclitaxel. Substitution of docetaxel for paclitaxel in these platinum-containing regimens is also being investigated. The taxanes also exhibit activity against ovarian cancer in patients previously exposed to platinum agents. These agents may also be administered intraperitoneally for local therapy of metastatic ovarian cancer. Although docetaxel and paclitaxel are often considered similar in activity and tolerability, this review emphasises the fact that these agents are indeed different. Clinicians need to be familiar with the benefits and adverse events related to each agent in order to make informed, appropriate clinical decisions.