Cetuximab for the Treatment of Colorectal Cancer Jonker, Derek J; O'Callaghan, Chris J; Karapetis, Christos S ...
The New England journal of medicine,
11/2007, Letnik:
357, Številka:
20
Journal Article
Recenzirano
This open-label trial of the treatment of colorectal cancer with cetuximab, a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR), showed that among patients with ...colorectal cancer that expressed EGFR and that had failed to respond to other treatments, overall survival and progression-free survival were better in those receiving cetuximab than in those receiving best supportive care alone.
Among patients with colorectal cancer that expressed EGFR and that had failed to respond to other treatments, overall survival and progression-free survival were better in those receiving cetuximab than in those receiving best supportive care alone.
Colorectal cancer has a worldwide annual incidence of 917,000 and is the second leading cause of cancer-related death in Western nations.
1
The cytotoxic agents irinotecan, oxaliplatin, and the fluoropyrimidines, as well as bevacizumab, the antibody against vascular endothelial growth factor A, have increased the median survival of patients with advanced colorectal cancer,
2
–
9
but in most patients the disease is incurable.
Recent advances have led to the development of agents that specifically inhibit tumor growth. Epidermal growth factor receptor (EGFR) is often up-regulated in colorectal cancer. Cetuximab, a chimeric IgG1 monoclonal antibody that binds to the extracellular domain of EGFR, . . .
Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human ...epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer.
Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival.
A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% CI, 0.69 to 0.99; P = .038, adjusted for stratification factors; median 6.24 months v 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P = .023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; P = .004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2.
To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.
Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumour and haematological malignancies, including cancers of the testes, ovary, bladder, head and neck, ...oesophagus, stomach and lung, as well as lymphoma and osteosarcoma. Its non-specific targeting commonly results in adverse effects and toxicities affecting the gastrointestinal, renal, neurological and haematological systems even when administered at standard doses. Since cisplatin-related toxicities are dose-dependent, these may be more pronounced in the setting of a cisplatin overdose, resulting in significant morbidity and/or mortality. The incidence of cisplatin overdoses is unknown; however, early-phase clinical trials utilizing high-dose cisplatin, and case reports in the overdose setting have characterized the clinical features associated with cisplatin overdoses, highlighting some therapeutic strategies for consideration. To date, no published guidelines exist for managing a cisplatin overdose. The major toxicities of a cisplatin overdose include nausea and vomiting, renal insufficiency, electrolyte abnormalities, myelosuppression, ototoxicity, peripheral neuropathy, hepatotoxicity and retinopathy. Diarrhoea, pancreatitis, seizures and respiratory failure have also been reported. No specific antidote for cisplatin exists. Key management principles and strategies to lessen toxicities include renoprotection and enhancing drug elimination with aggressive intravenous hydration with or without the use of an osmotic diuretic, and avoidance of nephrotoxic medications. Sodium thiosulfate and plasmapheresis, with or without haemodialysis support, should be strongly considered. Close monitoring of clinical and laboratory parameters, and institution of supportive therapies, including antiemetics and haematopoietic colony stimulating factor support, are warranted. Based on the current literature, experimental therapies such as amifostine, ditiocarb sodium (diethyldithiocarbamate), acetylcysteine, fosfomycin and colestipol are of limited clinical effectiveness and remain investigational. This review serves to highlight the clinical spectrum of toxicities resulting from a cisplatin overdose, to critically appraise the available literature and to present a suggested algorithmic approach for the initial management of a cisplatin overdose.
This study examined the mutation status of the
K-ras
gene in colorectal tumors from patients who were enrolled in a trial of cetuximab, a monoclonal antibody against the epidermal growth factor ...receptor (EGFR). A survival benefit was found among patients with tumors bearing wild-type
K-ras
but not among patients with tumors bearing mutated
K-ras
. Wild-type
K-ras
is essential in transmitting signals initiated by EGFR.
This study examined the mutation status of the
K-ras
gene in colorectal tumors from patients who were enrolled in a trial of cetuximab. A survival benefit was found among patients with tumors bearing wild-type
K-ras
but not among patients with tumors bearing mutated
K-ras
.
A randomized trial (CO.17) conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) in collaboration with the Australasian Gastro-Intestinal Trials Group (AGITG) showed that among patients with colorectal cancer that had not responded to advanced chemotherapy, monotherapy with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), improved overall survival and progression-free survival and preserved the quality of life better than did best supportive care alone.
1
However, resistance to cetuximab was common: at the first assessment of disease response, the disease had progressed in more than 50% of treated patients.
K-ras
, a . . .
Abstract
Sodium-ion batteries are a promising battery technology for their cost and sustainability. This has led to increasing interest in the development of new sodium-ion batteries and new ...analytical methods to non-invasively, directly visualise battery chemistry. Here we report operando
1
H and
23
Na nuclear magnetic resonance spectroscopy and imaging experiments to observe the speciation and distribution of sodium in the electrode and electrolyte during sodiation and desodiation of hard carbon in a sodium metal cell and a sodium-ion full-cell configuration. The evolution of the hard carbon sodiation and subsequent formation and evolution of sodium dendrites, upon over-sodiation of the hard carbon, are observed and mapped by
23
Na nuclear magnetic resonance spectroscopy and imaging, and their three-dimensional microstructure visualised by
1
H magnetic resonance imaging. We also observe, for the first time, the formation of metallic sodium species on hard carbon upon first charge (formation) in a full-cell configuration.
A non-destructive and versatile chemical reduction method was used to dissolve and subsequently brominate few-layer graphene sheets (FLGs); the direct covalent attachment of bromine to the graphene ...framework was demonstrated by X-ray photoelectron spectroscopy (XPS). The brominated few-layer graphenes (FLG-Br) provide a convenient, stable, liquid-phase precursor, suitable for the synthesis of a variety of directly functionalised graphenes. As an example, the FLG-Br species was used to initiate atom transfer radical polymerisation (ATRP), to obtain poly(methyl methacrylate) (PMMA)-grafted graphene (FLG-PMMA), which was six times more dispersible in acetone than controls. In addition, the FLG-Br is active for nucleophilic substitution reactions, as illustrated by the preparation of methoxypolyethylene glycol (mPEG)- and OH-substituted derivatives. The products were characterised by thermogravimetric analysis coupled with mass spectrometry (TGA-MS), XPS and Raman spectroscopy. Grafting ratios (GR) for these polymer-grafted materials varied between 6 and 25%; even at these GRs, all graphene derivatives showed increased solubility in organic solvents.
Chemical functionalisation is one of the most active areas of graphene research, motivated by fundamental science, the opportunities to adjust or supplement intrinsic properties, and the need to ...assemble materials for a broad array of applications. Historically, the primary consideration has been the degree of functionalisation but there is growing interest in understanding how and where modification occurs. Reactions may proceed preferentially at edges, defects, or on graphitic faces; they may be correlated, uncorrelated, or anti-correlated with previously grafted sites. A detailed collation of existing literature data indicates that steric effects play a strong role in limiting the extent of reaction. However, the pattern of functionalisation may have important effects on the resulting properties. This article addresses the unifying principles of current graphene functionalisation technologies, with emphasis on understanding and controlling the locus of functionalisation.
Chemical functionalisation is one of the most active areas of graphene research, motivated by both fundamental science and the opportunities to adjust or supplement intrinsic properties. There is increasing interest in understanding and controlling the locus of reaction.
PURPOSE
Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often ...overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer.
PATIENTS AND METHODS
Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival.
RESULTS
A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% CI, 0.69 to 0.99; P = .038, adjusted for stratification factors; median 6.24 months v 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P = .023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; P = .004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2.
CONCLUSION
To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.
Sodium ion batteries are a promising alternative to current lithium ion battery technology, providing relatively high capacity and good cycling stability at low cost. Hard carbons are today the ...anodes of choice but they suffer from poor rate performance and low initial coulombic efficiency. To improve the understanding of the kinetics of sodium mobility in these materials, muon spin rotation spectroscopy and density functional theory calculations were used to probe the intrinsic diffusion of sodium in a characteristic hard carbon sample. This revealed that atomic diffusion between sites is comparable to that observed in transition metal oxide cathode materials in sodium ion batteries, suggesting that the poor rate performance is not limited by site-site jump diffusion rates. In addition, diffusion was observed in the sodium that is irreversibly stored during the first cycle, suggesting that some of these sodium atoms are not immobilised in the solid electrolyte interface (SEI) layer but are still blocked from long range diffusion, thereby rendering the sodium electrochemically inactive.
Sodium ion batteries are a promising alternative to current lithium ion battery technology, providing relatively high capacity and good cycling stability at low cost.
Purpose
This study was designed to examine quality of life and fatigue in colorectal cancer survivors meeting and not meeting public health exercise guidelines.
Methods
A Canadian provincial cancer ...registry identified colorectal cancer survivors who were mailed a questionnaire that assessed self-reported exercise, quality of life (Functional Assessment of Cancer Therapy - Colorectal), fatigue, medical, and demographic variables.
Results
Completed questionnaires were received from 413 (61.3 percent) eligible colorectal cancer survivors. Only 25.9 percent of colorectal cancer survivors reported meeting exercise guidelines. Colorectal cancer survivors meeting public health exercise guidelines reported clinically and significantly better quality of life (mean difference, 6; 95 percent confidence interval, 2.3–9.8;
P
= 0.002) and fatigue (mean difference = 5.2; 95 percent confidence interval, 2.9–7.5;
P
< 0.001). Differences remained after adjusting for medical and demographic factors. Cancer site (
i.e.
, colon
vs.
rectal) was the only variable to moderate this association (
P
< 0.05 for interaction).
Conclusions
Colorectal cancer survivors meeting public health exercise guidelines reported significantly and meaningfully better quality of life and fatigue scores than colorectal cancer survivors who did not meet guidelines. Prospective observational studies and randomized, controlled trials are needed to further assess the causal nature of these relationships.
PDF
