IMPORTANCE There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy. OBJECTIVE To determine the effect of duloxetine, 60 mg daily, on average pain severity. ...DESIGN, SETTING, AND PATIENTS Randomized, double-blind, placebo-controlled crossover trial at 8 National Cancer Institute (NCI)–funded cooperative research networks that enrolled 231 patients who were 25 years or older being treated at community and academic settings between April 2008 and March 2011. Study follow-up was completed July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligibility required that patients have grade 1 or higher sensory neuropathy according to the NCI Common Terminology Criteria for Adverse Events and at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment. INTERVENTIONS The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of duloxetine or placebo daily for 4 additional weeks. MAIN OUTCOME MEASURES The primary hypothesis was that duloxetine would be more effective than placebo in decreasing chemotherapy-induced peripheral neuropathic pain. Pain severity was assessed using the Brief Pain Inventory-Short Form “average pain” item with 0 representing no pain and 10 representing as bad as can be imagined. RESULTS Individuals receiving duloxetine as their initial 5-week treatment reported a mean decrease in average pain of 1.06 (95% CI, 0.72-1.40) vs 0.34 (95% CI, 0.01-0.66) among those who received placebo (P = .003; effect size, 0.513). The observed mean difference in the average pain score between duloxetine and placebo was 0.73 (95% CI, 0.26-1.20). Fifty-nine percent of those initially receiving duloxetine vs 38% of those initially receiving placebo reported decreased pain of any amount. CONCLUSION AND RELEVANCE Among patients with painful chemotherapy-induced peripheral neuropathy, the use of duloxetine compared with placebo for 5 weeks resulted in a greater reduction in pain. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00489411
Temozolomide (TMZ) is an oral alkylating agent that is regarded as a tolerable and effective drug. When combined with radiotherapy in patients with newly diagnosed glioblastoma, survival is ...significantly prolonged. This finding has led to widespread use of TMZ for patients with this disease. We summarize developing concerns regarding the use of TMZ, imaging of malignant gliomas, and the pharmacology of TMZ—mechanism of action, scheduling and strategies for overcoming resistance.
Background
Bevacizumab is widely used and may cause life-threatening bleeding. We attempted to identify clinical characteristics associated with central nervous system (CNS) hemorrhage in a broad ...population.
Methods
We performed a retrospective review of the FDA MedWatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Our search used keywords: bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke and brain.
Results
A total of 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1,041 reports described non-CNS bleeds. Median age was 62 years, and the primary cancers were consistent with indications for bevacizumab. Patients received a median of three (1–36) doses of bevacizumab prior to the bleed. Thirty percent had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. Death was reported as a complication of hemorrhage in 48 %. The most common predisposing factor for CNS bleeds was use of medications associated with bleeding, followed by thrombocytopenia.
Conclusion
In this database, 154 of 1,195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in two-thirds of cases.
Background/Aim
The number of coronavirus disease 2019 deaths and cases continues to increase globally. Novel therapies are urgently needed to treat patients with coronavirus disease 2019. We sought ...to provide a critical review of trials designed during the coronavirus disease 2019 pandemic. Our primary goal was to provide a critical review of the landscape of clinical trials designed to address the coronavirus disease 2019 pandemic. Specifically, we were interested in assessing the design of phase II/III and phase III interventional trials.
Methods
We utilized the ClinicalTrials.gov database to include trials registered between 1 December 2019 and 11 April 2021 to survey the current landscape of clinical trials for coronavirus disease 2019. Variables extracted included: National Clinical Trial number, title, location, sponsor, study type, start date, completion date, gender group, age group, primary outcome, secondary outcome, overall status, and associated references.
Results
About 57% of studies were interventional, 14.5% were phase III trials, and the majority of the therapeutic trials included hospitalized patients. There were 52 primary composite outcomes and 285 unique interventions spanning 10 drug classes. The outcomes, disease severity, and comparators varied substantially across trials, and the trials were often too small to be definitive.
Conclusion
These findings are relevant as we strongly advocate for global coordination of efforts through the use of common platforms that enable harmonizing of endpoints, collection of common key variables and clear definition of disease severity to have clinically meaningful results from clinical trials.
The adverse events associated with bevacizumab therapy are characterized, and the underlying pathophysiology, risk factors, frequency, and management of these events are described.
The adverse events ...associated with bevacizumab include hypertension, proteinuria, thromboembolism, impaired wound healing, bleeding, perforation, reversible leukoencephalopathy syndrome, skin rash, and infusion-related hypersensitivity reactions. Patients should be monitored for these events throughout the course of bevacizumab therapy. Hypertension is by far the most common adverse event associated with bevacizumab. Blood pressure should be routinely monitored, and hypertension should be medically managed with antihypertensive drugs as deemed appropriate during bevacizumab therapy. Patients should be monitored for proteinuria every three to four weeks, and bevacizumab should be discontinued with persistent proteinuria of >2+. Thromboembolic events, impaired wound healing, bowel and nasal septum perforation, and bleeding share similar pathophysiology. Thromboembolic events should be managed in accordance with guidelines established by the American College of Chest Physicians, and bevacizumab should be discontinued for new life-threatening venous or arterial thromboembolism. To minimize the risk of bleeding or impaired wound healing, bevacizumab should be started at least four weeks after surgery or discontinued for at least six to eight weeks before elective surgery. The management of other adverse events is more anecdotal, with relatively few reports of their occurrence with bevacizumab.
Many of the potential serious complications of bevacizumab can be averted by close monitoring of patient-specific variables, which should be measured at baseline and then at predetermined intervals throughout the course of therapy to maximize patient safety.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Purpose
Temozolomide (TMZ) is a widely used oral alkylating agent that has been associated with the development of severe hematologic adverse events (HAEs). Limited clinical information about HAEs is ...available.
Methods
We searched the FDA MedWatch database for TMZ and obtained all MedWatch reports on TMZ submitted to the FDA from November 1, 1997 to September 3, 2008. We defined major HAEs, namely agranulocytosis, aplasia, aplastic anemia (AA), leukemia (various), myelodysplastic syndrome (MDS), and lymphoma, and several minor HAEs.
Results
A total of 5,127 reports on 3,490 patients were submitted to MedWatch. Among these, we identified 112 cases of major HAEs. Of the 44 reported deaths, the major HAE was considered the cause in 32 cases. The median duration of TMZ treatment was 6 weeks 0.5–108 weeks. Seventy-six cases of AA or aplasia and 17 cases of leukemia represented the most common major HAE. Important minor HAEs were bone marrow failure and pancytopenia/pancytopenia-like with 325 combined cases; these reports are clinically similar to aplastic anemia.
Conclusion
The hematologic toxicity profile of TMZ differs from that of other alkylating agents. TMZ HAEs are emerging as significant concerns. Among alkylating agents, AA appears unique to TMZ, and the high rate warrants disclosure of patients. The duration of TMZ exposure prior to the development of AA may be quite short. The risk of AML/MDS is low, but the length of follow-up is insufficient to assess the true risk.
The EORTC–NCIC regimen for glioblastoma requires different dosing of temozolomide (TMZ) during radiation and maintenance therapy. This complexity is exacerbated by the availability of multiple TMZ ...capsule strengths. TMZ is an alkylating agent and the major toxicity of this class is dose-related myelosuppression. Inadvertent overdose can be fatal. The websites of the Institute for Safe Medication Practices (ISMP), and the Food and Drug Administration (FDA) MedWatch database were reviewed. We searched the MedWatch database for adverse events associated with TMZ and obtained all reports including hematologic toxicity submitted from 1st November 1997 to 30th May 2012. The ISMP describes errors with TMZ resulting from the positioning of information on the label of the commercial product. The strength and quantity of capsules on the label were in close proximity to each other, and this has been changed by the manufacturer. MedWatch identified 45 medication errors. Patient errors were the most common, accounting for 21 or 47 % of errors, followed by dispensing errors, which accounted for 13 or 29 %. Seven reports or 16 % were errors in the prescribing of TMZ. Reported outcomes ranged from reversible hematological adverse events (13 %), to hospitalization for other adverse events (13 %) or death (18 %). Four error reports lacked detail and could not be categorized. Although the FDA issued a warning in 2003 regarding fatal medication errors and the product label warns of overdosing, errors in TMZ dosing occur for various reasons and involve both healthcare professionals and patients. Overdosing errors can be fatal.
The purpose of our review is to summarize the clinical activity of oral targeted agents against brain metastases. This includes BRAF inhibitors (dabrafenib and vemurafenib), human epidermal growth ...factor receptor inhibitors (lapatinib, gefitinib, erlotinib, and afatinib), multi-kinase angiogenesis inhibitors (sorafenib, sunitinib, pazopanib, and vandetanib), and ALK/c-MET (crizotinib) and ALK/IGF-1 (ceritinib) inhibitors. Effective systemic therapies are needed for long-term benefit in brain metastases and documentation of intracranial activity for many therapies is poor. Our review provides a summary of the literature with pertinent data for clinicians. This is needed as subjects with brain metastases are often prevented from enrolling in clinical trials and investigations focused on systemic therapies for brain metastases are rare.
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