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)

Renal cell carcinoma is the most common form of kidney cancer worldwide, and is associated with poor survival. Approximately a third of patients diagnosed with renal cell carcinoma present with metastatic disease and a further third experience recurrence following treatment for localized disease. Until recently, the cytokines interferon-alpha and interleukin-2 were the only effective treatments available for metastatic renal cell carcinoma and were associated with a modest increase in survival in a limited subset of patients. The prognosis for metastatic renal cell carcinoma has dramatically improved with the development of novel targeted agents including the oral tyrosine kinase inhibitors, sunitinib and sorafenib. However, renal cell carcinoma and the therapies used to treat patients with renal cell carcinoma are associated with a range of symptoms and treatment-related adverse events which contribute to the burden of disease. Common adverse events associated with targeted agents include fatigue, gastrointestinal and skin-associated toxicities. These adverse events, while mostly mild and manageable, affect the patients' health-related quality of life. As this review of the available quality of life data shows, assessment of the impact of the disease and its treatment on health-related quality of life may influence the choice of treatment and highlights the importance of incorporating patient-reported outcomes in clinical trials.
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PMID:Quality of life in patients with metastatic renal cell carcinoma: the importance of patient-reported outcomes. 1969 88

Sunitinib is an oral oxindole multitargeted kinase inhibitor that inhibits certain receptor tyrosine kinases (RTKs). These include vascular endothelial growth factor receptors (VEGFR type 1 and 2), platelet-derived growth factor receptors (PDGFR-alpha and PDGFR-beta), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 (FLT3), glial cell-line derived neurotrophic factor receptor (RET) and the receptor of macrophage-colony stimulating factor (CSF1R). Examination of the antitumor effect of sunitinib in a variety of cell lines in vitro suggested an antiproliferative activity that is dependent on the presence of constitutively active RTK targets. The use of sunitinib as first-line therapy in advanced renal cell carcinoma (RCC) has improved the overall survival compared with that observed after cytokine therapy, while its administration in patients with gastrointestinal stromal tumors (GISTs) after progression or intolerance to imatinib achieved an objective response of 7%. Sunitinib is currently approved for the treatment of GISTs in this setting, and as first-line therapy for the treatment of advanced RCC. The relatively long half-life of sunitinib and its major metabolite allow for a once-daily dosing schedule. An interesting antitumor activity of sunitinib was reported in phase II studies of patients with a variety of malignancies, such as hepatocellular cancer, pancreatic neuroendocrine tumors, and non-small cell lung cancer; results of phase III studies are urgently anticipated. Fatigue is one of the most common adverse effects of sunitinib, as 50-70% of patients with advanced RCC and GIST complained of this adverse effect. Other adverse effects are diarrhea, anorexia, nausea and vomiting, oral changes and bleeding events. Most toxicities are reversible and should not result in discontinuation of sunitinib. If necessary, dose adjustments or interruptions should be made. Hypothyroidism has been described in the first 2 weeks of sunitinib therapy and its incidence increases progressively with the duration of therapy. Sunitinib may exert its hypertensive activity through a direct effect on the vasculature, while its most important cardiac adverse effect is left ventricular dysfunction. A variety of skin adverse effects have been described with the use of sunitinib such as hand-foot syndrome, yellow discoloration of the skin, dry skin, subungual splinter hemorrhages, acral erythema, and generalized skin rashes. Administration of sunitinib in the adjuvant and neoadjuvant setting of patients with RCC and of its combination with chemotherapy and other targeted therapies are currently under intense investigation.
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PMID:Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies. 1989 79

Approximately 40-50% of glioblastomas (GBM) overexpress epidermal growth factor receptor (EGFR). Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor active against refractory GBM. Patients with non-small cell lung cancer and > or =grade 2 erlotinib-induced rash have improved survival. This phase 2 study assessed the efficacy and safety of concurrent radiation therapy (RT) and temozolomide with pharmacodynamic dose escalation of erlotinib in patients with newly diagnosed GBM. Patients received RT 60 Gy in 30 fractions with concurrent temozolomide 75 mg/m(2)/day x 42 days, followed in four weeks by temozolomide 150-200 mg/m(2)/day x 5, every 28 days for 12 cycles. Patients received erlotinib, 50 mg/day and increased by 50 mg/day every 2 weeks until the occurrence of grade 2 rash or to a maximum dose of 150 mg/day, from day 1 until disease progression. Twenty-seven patients were treated in this study. Twenty-two (81%) patients came off study for progressive disease (18 [67%]) or adverse events (4 [15%]). Eighteen patients (67%) have died. Median progression-free survival was 2.8 months, and the median overall survival was 8.6 months. Five patients remain on study with a median follow-up of 16 months. Grade 3/4 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and febrile neutropenia. There were four deaths on study, three definitely treatment-related; therefore, the trial was terminated after accrual of 27 of 30 planned patients. Erlotinib co administered with RT and temozolomide was not efficacious and had an unacceptable toxicity.
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PMID:Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. 1996 Feb 28

The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.
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PMID:Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation. 2019 36

The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib, a multi-targeted tyrosine kinase inhibitor, against vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor-alpha and -beta, and c-Kit, in recurrent glioblastoma. Patients with < or =2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-week cycles without planned interruptions. Brain magnetic resonance imaging and clinical reassessment were made every 8 weeks. The primary endpoint was efficacy as measured by 6-month progression-free survival (PFS6). Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued. Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose reduction. Two patients had a partial radiographic response by standard bidimensional measurements, whereas 9 patients (6 at the 8-week point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% reduction in tumor. The median PFS was 12 weeks (95% confidence interval [CI]: 8-14 weeks) and only 1 patient had a PFS time > or =6 months (PFS6 = 3%). Thirty patients (86%) had died and median survival was 35 weeks (95% CI: 24-47 weeks). Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents. Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses. ClinicalTrials.gov identifier: NCT00459381.
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PMID:Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). 2020 24

Myasthenia gravis (MG) is the most common autoimmune disorder of the neuromuscular junction and is clinically characterized by weakness and muscle fatigue. We have classified MG into 3 types on the basis of the antibody pattern. The first type associated with acetylcholine receptor (AChR) autoantibodies, which predominantly belong to IgG1 subclass and are measured by a conventional radioimmunoprecipitation assay with 125I-alpha-bungarotoxin. This subtype occurs in approximately 80% of patients with MG and leads to the loss of AChR number and function, mainly by complement-mediated destruction of the neuromuscular junction. Approximately 40% of patients with MG who have AChR antibodes have a thymoma as a paraneoplastic neurological syndrome. However, the role of antigen expression by thymomas is unclear. The second type of MG occurs in a proportion of "seronegative" patients who did not have AChR autoantibodies. These patients process IgG autoantibodies to muscle-specific tyrosine kinase (MuSK); these antibodies are predominantly of the IgG4 subclass but are not associated with complement-mediated damage to the neuromuscular junction or with the presence of thymomas. In most patients with MuSK antibodies, the symptoms of MG improve after plasma exchange; these patients show a good response to steroid and immunosuppressive drugs but a poor response to thymectomy. MG not associated with the presence of the 2 abovementioned pathogenic autoantibodies is classified as heterogeneous "double seronegative" MG. Our classification is superior to the present classifications with regard to the mechanism, treatment, and prognosis of the disease.
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PMID:[Pathogenic antibodies in myasthenia gravis]. 2042 Jan 82

Pazopanib is an oral, multi-targeted, tyrosine kinase inhibitor (TKI) that binds to the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and several other key proteins responsible for angiogenesis, tumor growth and cell survival. Pazopanib exhibited in vivo and in vitro activity against tumor growth and, in early clinical trials, was well tolerated with the main side effects being hypertension, fatigue and gastrointestinal disorders. Pazopanib showed clinical activity in several tumors including renal cell cancer (RCC), breast cancer, soft tissue sarcoma, thyroid cancer, hepatocellular cancer and cervical cancer. A phase III clinical trial in metastatic RCC patients showed a significant improvement in progression-free survival, leading to its approval in the US. In metastatic breast cancer, the combination of pazopanib with lapatinib was more effective than lapatinib alone. At the time of the current publication, pazopanib is being evaluated in more than 35 phase II and III trials.
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PMID:Pazopanib: Clinical development of a potent anti-angiogenic drug. 2045 72

Patients diagnosed with advanced gastrointestinal stromal tumor (GIST) are currently treated with oral tyrosine kinase inhibitors (TKIs). Imatinib mesylate is the standard first-line treatment, and sunitinib malate is administered second-line for patients who are intolerant or progress on imatinib. Imatinib has recently been approved for adjuvant treatment of GIST patients who have a significant risk for relapse. In both the metastatic and adjuvant settings, patients may be on these TKIs for many years. Low plasma imatinib levels have been reported to be associated with a short median time to progression of advanced GIST, stressing the importance of maintaining optimal drug levels. We summarize management of the most frequent and clinically significant adverse effects of imatinib and sunitinib in the treatment of GIST in the context of current guidelines, published literature, and the experience of three large GIST referral centers. The adverse events reviewed include nausea and vomiting, diarrhea, skin rash, musculoskeletal complaints, fatigue, hemorrhage, edema, hand-foot skin reaction, skin and hair discoloration, mucositis, hypertension, cardiac toxicity, hypothyroidism, liver transaminase changes, and hematological toxicity of imatinib and sunitinib. Potential drug-drug interactions with each respective agent are also discussed. With prudent use of supportive care measures, many side effects can be managed without dose reduction or interruption of treatment. On the other hand, individualized tailoring of the dose is often required to manage severe toxicity, such as painful hand-foot skin reactions, fatigue, hepatotoxicity, or cardiac toxicity. Management of many TKI-related adverse effects require further evaluation in prospective clinical trials.
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PMID:Practical management of tyrosine kinase inhibitor-associated side effects in GIST. 2057 50

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens.
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PMID:Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. 2071 91

What's known on the subject? and What does the study add? The side-effect of targeted agents is known. The clinician should be aware of the side-effects of targeted agents and how to prevent/diminish them, particularly in sequential and combination therapies. The aim of this review is to help physicians tailor targeted treatments for advanced renal cell carcinoma to suit patient needs and ensure maximum overall duration of response to therapy by providing a summary of the frequency and time of onset of adverse events (AEs) and by raising awareness of AE profiles. A PubMed literature search was performed, and papers on targeted therapy-related AEs were reviewed. The frequency, severity and management of targeted therapy-related AEs are discussed. Manageable AEs commonly reported with all the approved targeted agents include: fatigue, gastrointestinal disorders (diarrhoea, nausea, vomiting), hypertension, skin and subcutaneous tissue disorders. Life-threatening AEs are less common than manageable AEs and are usually class specific. Data suggest that long-term treatment with well-established targeted agents does not result in increased or unexpected AEs. Caution is required with regard to the long-term use of newer targeted agents for which there are no long-term tolerability data or clinical experience. Studies have reported that the type and frequency of observed AEs associated with sequential tyrosine kinase inhibitor (TKI) use are similar to those reported in the literature for TKI monotherapy. Having an awareness of the AE profiles of targeted agents allows the development of effective management strategies. Generally, more extensive clinical experience has accumulated, and AE profiles are more predictable, for well-established targeted agents.
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PMID:Adverse events from targeted therapies in advanced renal cell carcinoma: the impact on long-term use. 2125 Nov 88


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