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)

Multiple myeloma (MM), a malignancy of the plasma cells, accounts for an estimated 14% of all newly diagnosed hematologic malignancies. Advances in chemotherapy and stem cell transplantation have improved survival rates, but MM remains incurable. Bortezomib (Velcade, Millennium Pharmaceuticals, Inc., Cambridge, MA), a first-in-class proteasome inhibitor, has been approved for patients with MM who have received at least two prior treatments and have demonstrated disease progression on the most recent one. During clinical trials, most side effects were manageable with standard interventions. The most common toxicities were asthenic conditions (fatigue, malaise, and weakness), gastrointestinal disturbances (nausea, vomiting, diarrhea, and constipation), thrombocytopenia, peripheral neuropathy, pyrexia, and anemia. Supportive therapies and strategies for side-effect management can prevent worsening of these symptoms, thereby avoiding dose reductions and treatment delays. Oncology nurses play a key role in ensuring the proper and safe administration of bortezomib and often are the first to identify the signs of side effects. Patient education about anticipated side effects and close monitoring of patients can lead to symptom management interventions that are essential to patient comfort and safety.
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PMID:Bortezomib, a newly approved proteasome inhibitor for the treatment of multiple myeloma: nursing implications. 1551 81

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.
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PMID:Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. 1562 43

Bortezomib, as a single agent and in combination with dexamethasone, was examined as first-line treatment in 32 consecutive patients with untreated symptomatic multiple myeloma. Patients received bortezomib 1.3 mg/m(2) for a maximum of six 3-week cycles; oral dexamethasone 40 mg was added if a less than partial response (PR) was achieved after two cycles or a less than complete response (CR) was achieved after four cycles. The response rate (CR + PR) was 88%, with undetectable paraprotein (CR) in 6%, and detectable by immunofixation only in 19% [near (n)CR]. All 32 patients completed the first two cycles of bortezomib alone, of whom 3% achieved CR, 9% nCR, and 28% PR. Ten patients received single-agent bortezomib on study, and dexamethasone was added in 22, leading to 15 improved responses. The most common adverse events >/=grade 2 included sensory neuropathy (31%), constipation (28%), myalgia (28%) and fatigue (25%). Sensory neuropathy grade 2 or 3 was reversible within a median of 3 months in five of 10 patients. Bortezomib treatment did not affect stem cell mobilization in eight or transplantation in six patients. Bortezomib alone or in combination with dexamethasone is an effective induction therapy with a high CR and nCR rate and manageable toxicities in previously untreated patients with myeloma.
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PMID:Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. 1595 4

(1) First-line treatment of multiple myeloma depends first and foremost on the patient's age. There is no standard treatment for relapses and the median survival time after the first relapse is only 12 to 15 months. (2) Bortezomib, a cytotoxic agent, inhibits the 26S proteasome involved in protein breakdown in mammalian cells. It is licensed for use in myeloma after multiple treatment failure. (3) Three dose-finding studies showed some effects of 1 mg/m2 and 1.3 mg/m2 bortezomib administered twice a week for two weeks, with each course followed by a 10-day treatment-free period. It is not known whether 1.3 mg/m2 is more effective than 1 mg/m2. (4) In a non comparative trial that included 202 patients with multidrug-resistant myeloma, progression-free survival time increased to a median of 6.6 months (compared to 3.3 months after previous relapses), and the median overall survival time was 7 months in the 75% of patients who did not respond and more than 15 months in the 25% of responders. However, given the heterogeneous nature of the study population the evidence from this trial is rather weak. (5) An unblinded comparative trial including 54 patients failed to show whether bortezomib 1.3 mg/m2 was more effective than bortezomib 1 mg/m2 in terms of clinical outcome. Another comparative trial including 669 patients indicated that bortezomib was more effective than dexamethasone in terms of the median time to disease progression (5.7 months versus 3.6 months). (6) Animal studies indicate that bortezomib is cardiotoxic and neurotoxic, and that the interval between the maximal tolerated dose and the fatal dose is very small. Experience with bortezomib use is too limited to know the possible clinical repercussions of these experimental findings. (7) Adverse effects were frequent and varied in clinical trials. They included fatigue, nausea and vomiting, diarrhea, anemia, thrombocytopenia and peripheral neuropathies. They affected 30% to 60% of patients overall, and were severe in about 10% to 20% of patients. Other adverse effects included hypotension, fever, headache, pain and dehydration. (8) Bortezomib is metabolised by cytochrome P 450 isoenzyme 3A4, and this implies a high risk of drug-drug interactions. (9) Each vial of bortezomib contains more of the drug than is needed for one injection. This is not only wasteful, but also carries a risk of overdosing, with potentially serious consequences, should the entire contents be injected by mistake. (10) Bortezomib may be used as a last resort in some patients with multiple myeloma, but the individual risk-benefit balance must be carefully weighed in each case.
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PMID:Bortezomib: new drug. A last resort in myeloma: modest efficacy, major risks. 1598 89

(1) When multiple myeloma relapses more than one year after initial treatment, the median survival time is only 12 to 15 months. (2) Bortezomib is a cytotoxic agent that inhibits the 26S proteasome, a complex involved in intracellular protein breakdown in mammals. Bortezomib was initially licensed for the treatment of myeloma after multiple treatment failure; its indications were subsequently modified to include second-line treatment. (3) Second-line bortezomib therapy has not been compared with haematopoietic stem cell grafting, a treatment with documented efficacy. (4) An unblinded comparative trial involving 54 patients requiring second-line treatment showed that bortezomib at a dose of 1.3 mg/m to the 2nd power (twice a week for two weeks, followed by a 10 day rest period) was significantly more effective than a dose of 1 mg/m to the 2nd power in terms of the median survival time (not determined in the 1.3 mg group, versus 26.7 months in the 1 mg group) and the median time to disease progression (11.7 versus 4.2 months). (5) Among 251 patients in whom first-line treatment had failed, bortezomib was significantly more effective than dexamethasone: the one-year survival rate was 80% versus 66% on dexamethasone, and the progression-free survival time was 6.2 months versus 3.5 months. (6) Adverse effects occurred in 30% to 60% of patients enrolled in clinical trials, and were severe in about 10% to 20% of patients. They mainly included fatigue, nausea and vomiting, diarrhoea, anaemia, thrombocytopenia, and peripheral neuropathy. Animal studies indicated a possible risk of cardiotoxicity, and cases of cardiac arrhythmias and conduction disorders were observed in clinical trials. (7) Bortezomib is metabolised by the cytochrome P450 isoenzyme CYP3A4, with a high risk of interactions. (8) The vials contain an excessive amount of this costly drug, creating a risk of inadvertent overdose and leading to unnecessary waste. (9) In practice, bortezomib is an alternative to steroid therapy for patients with multiple myeloma in whom first-line treatment has failed and who do not qualify for stem cell grafting. The choice of treatment must be discussed with the patient, after providing thorough information on the likely benefits and risks
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PMID:Bortezomib: new indication. Second-line treatment of myeloma: limited efficacy, major risks. 1676 98

Although multiple myeloma (MM) remains an incurable disease, its treatment has improved over the past decade. This improvement has been at least in part due to the introduction of novel antimyeloma agents with new mechanisms of action, including those that target both myeloma cells and the tumor microenvironment, with antiangiogenic and immunomodulatory properties. Among these drugs, bortezomib (Velcade), a selective proteasome inhibitor, has been approved for the treatment of relapsed and refractory MM patients after one line of therapy. The toxicity profile of bortezomib includes gastrointestinal symptoms, fatigue, thrombocytopenia, peripheral neuropathy, postural hypotension, as well as some uncommon events. A patient with relapsed MM who developed recurrent bortezomib-induced rhabdomyolysis is reported. To our knowledge, this adverse event has not been previously described is this context.
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PMID:Bortezomib-induced rhabdomyolysis in multiple myeloma. 1701 40

In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.
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PMID:Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. 1714 84

A phase 2 trial was performed to study the combination of bortezomib (VELCADE) with intermediate-dose dexamethasone (DEX), and continuous low-dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma (MM). Fifty-four patients with advanced MM were enroled to receive eight 3-week treatment cycles with bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, followed by three 5-week cycles with bortezomib 1.3 mg/m(2) on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and 8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event-free survival was 12 months, with a median overall survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory.
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PMID:Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. 1789 40

Multiple myeloma is the second most common hematologic malignancy and remains incurable, despite advances in chemotherapy and stem cell transplantation. Bortezomib, a novel proteasome inhibitor, is approved for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. In the assessment of proteasome inhibition for extending remissions phase III trial of bortezomib versus high-dose dexamethasone, bortezomib led to significantly longer survival and time to progression and higher response rate in patients with relapsed multiple myeloma. The principal adverse events were gastrointestinal effects, fatigue, transient thrombocytopenia, and reversible peripheral neuropathy. The side effect profile of bortezomib is extensively characterized, predictable, and generally manageable; retreatment or extended bortezomib therapy seems well tolerated. Nurses play a unique role in bortezomib treatment: they are often closest to the patients and are most able to educate patients about side effects and, if necessary, take appropriate action, independently or collaboratively with healthcare team members. In this review, we present the latest efficacy and safety data for bortezomib in relapsed multiple myeloma and characterize common side effects associated with bortezomib and the implications for nursing. We also highlight practical strategies for preventing and managing side effects, thereby enhancing the clinical benefit of bortezomib-based therapies to patients.
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PMID:Expanding role of bortezomib in multiple myeloma: nursing implications. 1845 81

The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.
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PMID:An EORTC phase I study of Bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer. 1880 14


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