Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sorafenib is a small molecule inhibitor of several kinases involved in tumour proliferation and tumour angiogenesis including Raf, VEGFR and platelet derived growth factor receptor. In vivo Raf kinase inhibition has been observed in pharmacodynamic studies. Sorafenib is one of several VEGF-targeting compounds with recently demonstrated substantial anti-tumour effects in metastatic renal cell carcinoma. Delay in time to disease progression has been demonstrated in cytokine-refractory metastatic renal cell carcinoma, and further investigation is ongoing in a wide variety of tumour types. Sorafenib is well tolerated, with common toxicities including rash, diarrhoea, hand-foot skin reaction, fatigue and hypertension, when administered as the standard dose of 400 mg b.i.d.
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PMID:Sorafenib. 1650 17

Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer.
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PMID:Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. 1747 Jun 85

Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.
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PMID:Sorafenib and sunitinib: novel targeted therapies for renal cell cancer. 1765 13

Diagnosis of renal cell carcinoma (RCC) frequently occurs at advanced stages, severely limiting the success of treatment, and median survival is barely more than a year. Previously, treatment of renal cancer was limited to nephrectomy or immunotherapy (interleukin or interferon-alpha), which was effective in a small subset of patients but often was accompanied by severe side effects. New orally administered targeted therapies have become available, offering broader benefits to patients with advanced RCC. Sorafenib is an oral, multikinase inhibitor recently approved by the U.S. Food and Drug Administration as treatment for advanced RCC based on its extension of median progression-free survival from 12-24 weeks. Oncology nurses must ensure patient adherence and manage side effects of emerging treatments. This article reviews the management of skin rash, hand-foot skin reaction, hypertension, diarrhea, and fatigue in patients receiving sorafenib. In addition, a case study of a patient receiving sorafenib is presented.
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PMID:Sorafenib: a promising new targeted therapy for renal cell carcinoma. 1856 57

Sorafenib is a novel oral multikinase inhibitor that targets Raf serine/threonine and receptor tyrosine kinases, and inhibits tumor cell proliferation and angiogenesis. We have conducted a phase I study of sorafenib to determine the safety, tolerability, pharmacokinetics, and potential efficacy of this agent in 31 Japanese patients with advanced refractory solid tumors. Sorafenib (100-600 mg) was given as a single dose followed by a 7-day wash-out period, and then administrated twice daily (bid). The most frequent drug-related adverse events were rash/desquamation (61%), hand-foot skin reactions (39%), diarrhea (36%), and elevations of serum lipase (36%) and amylase (26%) levels. Dose-limiting toxicities (DLTs) were grade 3 diarrhea at 200 mg bid and grade 3 fatigue at 600 mg bid. Grade 3 and 4 pancreatic enzyme elevations were observed at 200-600 mg bid, but they were not deemed dose-limiting because they were asymptomatic and were not associated with pancreatitis or chronic damage to the pancreas. The AUC and C(max) of sorafenib increased linearly with dose up to 400 mg bid. Partial responses were observed in one of 10 patients with non-small cell lung cancer and one of three patients with renal cell carcinoma. In conclusion, sorafenib 400 mg bid was well tolerated in Japanese patients with advanced refractory solid tumors. The recommended dose for future clinical trials is 400 mg bid.
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PMID:Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors. 1847 34

Sorafenib (BAY 43-9006) is a novel oral bis-aryl urea compound originally developed as an inhibitor to RAF kinase for its anti-proliferative property. It also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-2/3, Flt-3/ and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Phase I studies demonstrated that sorafenib was well tolerated, and the recommended phase II dose was 400 mg twice daily continuously. Common toxicities included skin toxicity (rash and hand-foot syndrome), gastrointestinal toxicities (nausea and diarrhea) and fatigue. Anti-tumor activities were observed in multiple tumors types including renal cell carcinoma and hepatocellular carcinoma. Randomized phase III studies in these tumor types are ongoing, and results are eagerly waited.
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PMID:Sorafenib (BAY 43-9006): review of clinical development. 1866 47

Sorafenib (Nexavar) is an orally active multikinase inhibitor that is approved in the EU for the treatment of hepatocellular carcinoma. Monotherapy with sorafenib prolongs overall survival and delays the time to progression in patients with advanced hepatocellular carcinoma who are not candidates for potentially curative treatment or transarterial chemoembolization. Sorafenib is generally well tolerated in patients with advanced hepatocellular carcinoma. Thus, sorafenib represents an important advance in the treatment of advanced hepatocellular carcinoma and is the new standard of care for this condition. The bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis. In vitro, dose-dependent inhibition of cell proliferation and induction of apoptosis was seen with sorafenib in human hepatocellular carcinoma cells lines. Sorafenib demonstrated dose-dependent antitumour activity in a murine xenograft model of human hepatocellular carcinoma. Steady-state plasma concentrations were reached within 7 days in patients with advanced, refractory solid tumours who received twice-daily oral sorafenib. Metabolism of sorafenib occurs primarily in the liver and is mediated via cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase 1A9. In advanced hepatocellular carcinoma, differences in sorafenib pharmacokinetics between Child-Pugh A and B patients were not considered clinically significant. Sorafenib may be associated with drug interactions. For example, sorafenib exposure was reduced by an average 37% with concomitant administration of the CYP3A4 inducer rifampicin (rifampin); sorafenib concentrations may also be decreased by other CYP3A4 inducers. Monotherapy with oral sorafenib 400 mg twice daily prolonged median overall survival and delayed the median time to progression in patients with advanced hepatocellular carcinoma, according to the results of two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial). There was no significant difference between sorafenib and placebo recipients in the median time to symptomatic progression in either trial. The vast majority of patients included in these trials were Child-Pugh A. Combination therapy with sorafenib plus doxorubicin did not delay the median time to progression to a significant extent compared with doxorubicin alone in patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II trial. However, the median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone. Combination therapy with sorafenib plus tegafur/uracil or mitomycin also showed potential in advanced hepatocellular carcinoma, according to the results of noncomparative trials. Monotherapy with oral sorafenib was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse effect profile; diarrhoea and hand-foot skin reaction were consistently the most commonly occurring drug-related adverse events in clinical trials. In the SHARP trial, drug-related adverse events of any grade occurring in significantly more sorafenib than placebo recipients included diarrhoea, hand-foot skin reaction, anorexia, alopecia, weight loss, dry skin, abdominal pain, voice changes and 'other' dermatological events. A similar tolerability profile was seen in the Asia-Pacific trial. As expected given the addition of a chemotherapy agent, the adverse event profile in patients with advanced hepatocellular carcinoma who received combination therapy with sorafenib plus doxorubicin differed somewhat to that seen with sorafenib monotherapy in the SHARP trial. In patients receiving sorafenib plus doxorubicin, the most commonly occurring all-cause adverse events (all grades) included fatigue, neutropenia, diarrhoea, elevated bilirubin levels, abdominal pain, hand-foot skin reaction, left ventricular dysfunction, hypertension and febrile neutropenia.
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PMID:Sorafenib: a review of its use in advanced hepatocellular carcinoma. 1922 77

Despite their inherent selectivity, targeted therapies such as tyrosine kinase inhibitors (TKIs) can cause unusual adverse effects. Sunitinib and sorafenib are multitargeted TKIs that have been demonstrated to induce hypothyroidism and thyroid dysfunction. Retrospective studies indicate that sunitinib can induce hypothyroidism in 53-85% of patients, and in prospective studies this complication has been reported in 36-71% of patients. Sorafenib has been reported to be responsible for hypothyroidism in 18% of patients with metastatic renal-cell carcinoma. Furthermore, imatinib and sunitinib seem to increase the requirement of levothyroxine in hypothyroid patients. The management of thyroid dysfunction and possible related symptoms, such as fatigue, represents a challenge to oncologists. We propose a diagnostic and therapeutic algorithm for the management of TKI-related hypothyroidism. Prospective trials are needed to define the incidence of overt and subclinical hypothyroidism and thyroid dysfunction during therapy with sunitinib, sorafenib and potentially other TKIs. The safety and efficacy, and optimal dosing and timing of starting replacement therapy in patients affected by TKI-related hypothyroidism need accurate appraisal and should be evaluated prospectively in appropriately designed trials.
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PMID:Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. 1933 28

Sorafenib(Nexavar)is a multikinase inhibitor, with disruptive activity at intracellular C-RAF, B-RAF and mutant BRAF receptors, and extracellular C-KIT, FLT-3, VEGFR-2, VEGFR-3 and PDGFRb receptors. In the phase III study, as compared with placebo, treatment with sorafenib significantly prolonged progression free survival(PFS)in patients with advanced renal cell carcinoma in whom previous therapy has failed. Diarrhea, rash, fatigue, hand-foot skin reactions, and hypertension were the most common adverse events associated with sorafenib. As sorafenib was associated with similar rates of clinically manageable side effects in elderly patients as compared to younger patients, response rates to sorafenib in elderly patients were comparable to those of younger patients. Sorafenib was approved multinationally for the treatment of advanced and/or metastatic renal cell carcinoma. Sorafenib and sunitinib are reference standards of care for the treatment of advanced renal cell carcinoma and are recommended by current clinical guidelines. For the future, research of biomarker, adverse drug reaction, and combined regimens are needed to maximize the effects of molecular-targeted drugs.
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PMID:[Sorafenib(Nexavar)]. 1954 31

Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients.
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PMID:Sorafenib for the treatment of unresectable hepatocellular carcinoma. 1970 58


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