Medication errors involving oral chemotherapy

BACKGROUND:

Given the expanding use of oral chemotherapies, the authors set out to examine errors in the prescribing, dispensing, administration, and monitoring of these drugs.

METHODS:

Reports were collected of oral chemotherapy‐associated medication errors from a medical literature and Internet search and review of reports to the Medication Errors Reporting Program and MEDMARX. The authors solicited incident reports from 14 comprehensive cancer centers, and also collected incident reports, pharmacy interventions, and prompted clinician reports from their own center. They classified the type of incident, severity, stage in the medication use process, and type of medication error. They examined the yield of the various reporting methods to identify oral chemotherapy‐related medication errors.

RESULTS:

The authors identified 99 adverse drug events, 322 near misses, and 87 medical errors with low risk of harm. Of the 99 adverse drug events, 20 were serious or life‐threatening, 52 were significant, and 25 were minor. The most common medication errors involved wrong dose (38.8%), wrong drug (13.6%), wrong number of days supplied (11.0%), and missed dose (10.0%). The majority of errors resulted in a near miss; however, 39.3% of reports involving the wrong number of days supplied resulted in adverse drug events. Incidents derived from the literature search and hospital incident reporting system included a larger percentage of adverse drug events (73.1% and 58.8%, respectively) compared with other sources.

CONCLUSIONS:

Ensuring oral chemotherapy safety requires improvements in the way these drugs are ordered, dispensed, administered, and monitored. Cancer 2010. © 2010 American Cancer Society.     

Intracavital chemotherapy for peritoneal and pleural carcinomatosis with lipid-formulated anticancer agents

A clinical pilot study of intracavital chemotherapy with anticancer agents dissolved in lipids for malignant effusion in pleural and peritoneal cavity was performed. Seven patients with pleural or peritoneal metastases were treated with a cocktail of anticancer agents dissolved in Lipiodol individually administered via the intracavitary route. All the patients revealed cytological and physical improvement. Five patients responded completely and two responded partially; four patients were able to be discharged from hospital and no serious side effects were observed. Thus, this therapeutic tactic of using oily anticancer agents appeares to be promising for control of pleural and peritoneal carcinomatoses.     

Metallothionein and anticancer agents: the role of metallothionein in cancer chemotherapy

Summary Metallothioneins (MTs) are intracellular proteins containing the highest amount of thiol groups within the cytoplasm. These thiol groups are able to bind several cytotoxic agents, such as platinum compounds and alkylating agents. Increased levels of MT are one mechanism of resistance to these anticancer drugs, as intracytoplasmic binding of MT prevents the active molecules from reaching their target, the intranuclear DNA of tumor cells. MT synthesis can easily be induced by physiologic heavy metals such as zinc and copper. Pharmacological modulation of MT levels has been used to increase the MT pool in normal tissues and decrease their susceptibility to the toxicity of anticancer drugs. In the case of tumors arising in the brain, where the inducibility of MT synthesis is low, this approach would allow protection of normal tissues without decreasing the antitumor activity of the cytotoxic agents. The interaction of MT with cytotoxic agents is not limited to covalent binding. A correlation between MT synthesis and amplification of oncogenes such asras has been reported. Furthermore, the cytotoxic drugs are bound by MT after competition with zinc and copper; these metals are cofactors of numerous metalloenzymes, some of which are involved in the metabolism of nucleic acids. Competitive displacement of these metals might modify nucleic acid metabolism and influence cellular proliferation. On the other hand, increased MT levels could provide a zinc cofactor reserve that increases the cell's reparative potential when faced by DNA damage by cytotoxic agents. Although the physiologic role of MT in resistance to the cytotoxic effects of anticancer drugs remains unclear, a better understanding of the interaction between MT and chemotherapeutic agents may be important in the treatment of cancer.     

Carcinogenicity of anticancer agents

Chemotherapeutic treatment for cancer has been successful in prolonging survival but it has also been demonstrated that survivors of cancer patients who had received chemotherapy with alkylating agents have an increased risk of second malignancies, mostly acute non-lymphatic leukemia. The purpose of this paper is to show practical problems pertaining to the development and clinical use of anticancer agents in terms of prevention of second cancers.     

Targeting chemotherapy of hepatocellular carcinoma by arterial administration of anticancer agents dissolved in lipiodol

The lipid lymphographic agent, Lipiodol ultrafluid has been found to remain selectively in hepatocellular carcinoma. Using this characteristic nature of Lipiodol, a new targeting anticancer chemotherapy was devised. In order to achieve targeting anticancer chemotherapy and useful anticancer effects, anticancer drugs must be dissolved or suspended in Lipiodol and diffuse out from the Lipiodol gradually. Oily anticancer agents such as SMANCS dissolved in Lipiodol (SMANCS/Lipiodol), Mitomycin C in Lipiodol (MMC/Lipiodol), Aclarubicin in Lipiodol (ACR/Lipiodol) and a mixture of these were administered by catheterizing the celiac or hepatic artery under X-ray monitoring in 216 patients with hepatocellular carcinoma. Remarkable anticancer effects of this targeting chemotherapy were achieved, the serum AFP level and tumor size both showing a decrease in 91% of cases. The survival period of patients with unresectable hepatoma treated with the present protocol was definitely longer than the comparison group.     

Selected fatty acids as possible intermediates for selective cytotoxic activity of anticancer agents involving oxygen radicals

Both polyunsaturated fatty acids (PUFAs) and certain anticancer agents can generate peroxides leading to extensive lipid peroxidation. The link between peroxides, PUFAs and cell killing has been examined by testing the susceptibility of tumor cells to peroxides generated by PUFAs. Our results demonstrate that gammalinolenic, arachidonic and eicosapentaenoic acids are highly effective in killing human breast, lung, and prostate tumor cells while leaving normal cells viable. The availability of PUFAs and the role of lipoperoxidation are discussed with respect to the cytotoxic action of anticancer agents involving oxygen radicals. The results suggest that tumor cell susceptibility to lipid peroxides can be selectively modulated and manipulated by dietary PUFAs, especially those with 3 or more double bonds, and that the suggestion that non-selective toxicities of drugs are mediated by lipid peroxides must be viewed with caution.     

Pharmacokinetic variability of anticancer agents

The translation of advances in cancer biology to drug discovery can be complicated by pharmacokinetic variation between individuals and within individuals, and this can result in unpredictable toxicity and variable antineoplastic effects. Previously unrecognized variables (such as genetic polymorphisms) are now known to have a significant impact on drug disposition. How can the pharmacokinetic variability of anticancer agents be reduced? This will require the understanding of correlations between pharmacokinetics and treatment outcomes, the identification of relevant patient parameters, mathematical modelling of individual and population pharmacokinetics, and the development of algorithms that will tailor doses to the individual patient.     

Aurora-kinase inhibitors as anticancer agents

Errors in mitosis can provide a source of the genomic instability that is typically associated with tumorigenesis. Many mitotic regulators are aberrantly expressed in tumour cells. These proteins could therefore make useful therapeutic targets. The kinases Aurora-A, -B and -C represent a family of such targets and several small-molecule inhibitors have been shown to block their function. Not only have these inhibitors advanced our understanding of mitosis, but, importantly, their in vivo antitumour activity has recently been reported. What have these studies taught us about the therapeutic potential of inhibiting this family of kinases?     

Radiation recall with anticancer agents

Radiation recall is an acute inflammatory reaction confined to previously irradiated areas that can be triggered when chemotherapy agents are administered after radiotherapy. It remains a poorly understood phenomenon, but increased awareness may aid early diagnosis and appropriate management. A diverse range of drugs used in the treatment of cancer has been associated with radiation recall. As most data come from case reports, it is not possible to determine the true incidence, but to date the antineoplastic drugs for which radiation recall reactions have been most commonly reported include the anthracycline doxorubicin, the taxanes docetaxel and paclitaxel, and the antimetabolites gemcitabine and capecitabine. Radiation recall is drug-specific for any individual patient; it is not possible to predict which patients will react to which drugs, and rechallenge does not uniformly induce a reaction. There are no identifiable characteristics of drugs that cause radiation recall, and thus, it is a possibility that must be kept in mind with use of any drug after radiotherapy, including those from new drug classes. Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized by prolonging the interval between completion of radiotherapy and initiation of chemotherapy.     

Genomic markers and anticancer chemotherapy

Worldwide research on the human genome exerts a major impact on medical science. The growing evidence that genetic polymorphisms in the metabolism, the disposition, and the targets of drugs can have an even greater influence on the efficacy and the toxicity led to the creation of a novel chemotherapeutic strategy, personalized medicine. Much effort has been directed toward identifying the indicators of individual response to drugs, and these studies have provided a variety of potent predictive markers of individual drug response, which include some significant markers in clinical practice with sufficient evidence. Personalized medicine based on the response prediction using genomic marker is increasingly being recognized as a practical treatment approach in cancer chemotherapy, and to be indispensable when molecular targeted drugs are involved in the therapy. Even so, the ingenious and intricate mechanism of individual drug response creates obstacles in predicting chemotherapeutic response: Multiple factors are involved in the mechanisms, and key factors for drug response vary significantly among individuals. DNA chip technology enables us to overview a huge number of gene expressions simultaneously, but gene expression profiles of drug sensitivity vary considerably even for the same drug, which shows the limited value of a static microarray-expression profile as a marker aimed at individualizing patient therapy. Selection of a set of truly significant genomic markers and understanding of their interplay are of key importance in prediction of individual response to drug therapies. Challenges to such biological complexity are now started to identify a better genomic marker. The contribution of genomic marker research to anticancer chemotherapy and problems of the day were reviewed.     

Genome research and anticancer chemotherapy

Worldwide research on the human genome is having a major impact on medical science and advanced medicine, although the detailed function and interaction of most genes remain unclear. The elucidation of human genome data makes it possible to take global views of biological processes and characteristics of cancer and individual drug response. This brings a number of new challenges such as genome based drug development and tailored cancer chemotherapy based on the individual genomic make-up. When a disease gene is identified, truly effective drugs targeting the genes can be developed. When biological characteristics such as polymorphism and gene expression profiles are closely related to drug response, an individually optimized drug therapy can be realized. cDNA microarray technology and new high-throughput single nucleotide polymorphism (SNP) screening offer great hope for such a global view by providing a systematic way to survey DNA and RNA variation. Evolutionary engineering techniques continue to be developed, which significantly promotes studies to understand molecular mechanisms causing diseases, novel disease genes, and genes related to drug response. Such progress in genome research and the functional analysis may revolutionize the anticancer chemotherapy world. The possible contribution of genome research to anticancer chemotherapy and problems of the day are reviewed herein.     

Novel antibodies as anticancer agents

In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.     

Cannabinoids: potential anticancer agents

Cannabinoids - the active components of Cannabis sativa and their derivatives - exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies. So, could cannabinoids be used to develop new anticancer therapies?     

Arsenic compounds as anticancer agents

In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation.     

Drug interactions with anticancer agents

Each anticancer agent has its own pharmacologic activities. Effect of anticancer agent may be influenced by the concomitant administration of another drug. In addition, patients with advanced cancer occasionally require other medications as well. These drugs can alter both the effects and adverse reactions of anticancer agents. Therefore, much attention must be placed on the interaction with anticancer agents. This paper summarizes drug interactions between anticancer agents and other drugs. Furthermore, clinical significance of these interactions will be discussed. It is hoped that this paper will provide more attention for the study of this problem.     

Microtubule-targeted anticancer agents and apoptosis

Over the past decade, significant progress has been made in our understanding of the biology of microtubule (MT) assembly into the mitotic spindle during mitosis and the molecular signaling and execution of the various pathways to apoptosis. In the same period, the microtubule-targeted tubulin-polymerizing agents (MTPAs), notably paclitaxel and taxotere, have come to occupy a central role in the treatment of a variety of human epithelial cancers. Following their binding to B-tubulin, MTPAs inhibit MT dynamic instability, cell cycle G2/M phase transition and mitotic arrest of cancer cells. MTPA-induced anti-MT and cell cycle effects trigger the molecular signaling for the mitochondrial pathway of apoptosis. This triggering is orchestrated through different molecular links and determined by the threshold for apoptosis that is set and controlled diversely in various cancer types. The complexity and regulatory potential of the links and the apoptosis threshold are integral to the transformed biology of the cancer cell. The emerging understanding of this biology and how it is influenced by treatment with MTPAs has highlighted novel strategies to further enhance the antitumor activity and overcome resistance to MTPA-induced apoptosis in cancer cells.     

Pharmacogenetics and pharmacogenomics of anticancer agents

Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made in the field of pharmacogenetics and pharmacogenomics using a five‐stage architecture, which includes 1) determining the role of genetics in drug response; 2) screening and identifying genetic markers; 3) validating genetic markers; 4) clinical utility assessment; and 5) pharmacoeconomic impact. Examples are provided to illustrate the identification, validation, utility, and challenges of these pharmacogenetic and pharmacogenomic markers, with the focus on the current application of this knowledge in cancer therapy. With the advance of technology, it becomes feasible to evaluate the human genome in a relatively inexpensive and efficient manner; however, extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside. CA Cancer J Clin 2009;59:42–55. © 2009 American Cancer Society.