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      Cardiotoxicity of Anticancer Drugs: The Need for Cardio-Oncology and Cardio-Oncological Prevention

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          Abstract

          Due to the aging of the populations of developed countries and a common occurrence of risk factors, it is increasingly probable that a patient may have both cancer and cardiovascular disease. In addition, cytotoxic agents and targeted therapies used to treat cancer, including classic chemotherapeutic agents, monoclonal antibodies that target tyrosine kinase receptors, small molecule tyrosine kinase inhibitors, and even antiangiogenic drugs and chemoprevention agents such as cyclooxygenase-2 inhibitors, all affect the cardiovascular system. One of the reasons is that many agents reach targets in the microenvironment and do not affect only the tumor. Combination therapy often amplifies cardiotoxicity, and radiotherapy can also cause heart problems, particularly when combined with chemotherapy. In the past, cardiotoxic risk was less evident, but it is increasingly an issue, particularly with combination therapy and adjuvant therapy. Today's oncologists must be fully aware of cardiovascular risks to avoid or prevent adverse cardiovascular effects, and cardiologists must now be ready to assist oncologists by performing evaluations relevant to the choice of therapy. There is a need for cooperation between these two areas and for the development of a novel discipline, which could be termed cardio-oncology or onco-cardiology. Here, we summarize the potential cardiovascular toxicities for a range of cancer chemotherapeutic and chemopreventive agents and emphasize the importance of evaluating cardiovascular risk when patients enter into trials and the need to develop guidelines that include collateral effects on the cardiovascular system. We also discuss mechanistic pathways and describe several potential protective agents that could be administered to patients with occult or overt risk for cardiovascular complications.

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          Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.

          Selective cyclooxygenase-2 (COX-2) inhibitors have come under scrutiny because of reports suggesting an increased cardiovascular risk associated with their use. Experimental research suggesting that these drugs may contribute to a prothrombotic state provides support for this concern. We reviewed all potentially serious cardiovascular events among 2035 patients with a history of colorectal neoplasia who were enrolled in a trial comparing two doses of celecoxib (200 mg or 400 mg twice daily) with placebo for the prevention of colorectal adenomas. All deaths were categorized as cardiovascular or noncardiovascular, and nonfatal cardiovascular events were categorized in a blinded fashion according to a prespecified scheme. For all patients except those who died, 2.8 to 3.1 years of follow-up data were available. A composite cardiovascular end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure was reached in 7 of 679 patients in the placebo group (1.0 percent), as compared with 16 of 685 patients receiving 200 mg of celecoxib twice daily (2.3 percent; hazard ratio, 2.3; 95 percent confidence interval, 0.9 to 5.5) and with 23 of 671 patients receiving 400 mg of celecoxib twice daily (3.4 percent; hazard ratio, 3.4; 95 percent confidence interval, 1.4 to 7.8). Similar trends were observed for other composite end points. On the basis of these observations, the data and safety monitoring board recommended early discontinuation of the study drug. Celecoxib use was associated with a dose-related increase in the composite end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure. In light of recent reports of cardiovascular harm associated with treatment with other agents in this class, these data provide further evidence that the use of COX-2 inhibitors may increase the risk of serious cardiovascular events. Copyright 2005 Massachusetts Medical Society.
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            Biomarkers in heart failure.

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              Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice.

              Gastrointestinal (GI) tract damage by chemotherapy or radiation limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberkühn to initiate the lethal GI syndrome. Here, we show in mouse models that microvascular endothelial apoptosis is the primary lesion leading to stem cell dysfunction. Radiation-induced crypt damage, organ failure, and death from the GI syndrome were prevented when endothelial apoptosis was inhibited pharmacologically by intravenous basic fibroblast growth factor (bFGF) or genetically by deletion of the acid sphingomyelinase gene. Endothelial, but not crypt, cells express FGF receptor transcripts, suggesting that the endothelial lesion occurs before crypt stem cell damage in the evolution of the GI syndrome. This study provides a basis for new approaches to prevent radiation damage to the bowel.
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                Author and article information

                Journal
                J Natl Cancer Inst
                jnci
                jnci
                JNCI Journal of the National Cancer Institute
                Oxford University Press
                0027-8874
                1460-2105
                6 January 2010
                6 January 2010
                6 January 2010
                6 January 2010
                : 102
                : 1
                : 14-25
                Affiliations
                Affiliations of authors: Oncology Research Division, MultiMedica Castellanza (VA), Oncology Research Division, Milan, Italy (AA); Istituto di Ricerca e Cura a Carattere Scientifico MultiMedica, Milan, Italy (AA, GP, RC, DMN); Cardiothoracic and Vascular Department, Istituto di Ricerca e Cura a Carattere Scientifico MultiMedica, Milan, Italy (FD); Chair of Cardiac Surgery, University of Milan “Statale”, Milan, Italy (FD); Department of Health Sciences, University of Genoa, Genoa, Italy (SDF); Department of Clinical and Biological Sciences, University of Insubria, Varese, Italy (DMN)
                Author notes
                Correspondence to: Adriana Albini, PhD, Oncology Research Division, Istituto di Ricerca e Cura a Carattere Scientifico MultiMedica, Via Fantoli 16/15, 20138 Milano, Italy (e-mail: adriana.albini@ 123456multimedica.it ).
                Article
                10.1093/jnci/djp440
                2802286
                20007921
                b2f7d3e5-846f-4b5b-9d4f-18b7e7df9a91
                © The Author 2009. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 April 2009
                : 9 October 2009
                : 4 November 2009
                Categories
                Review

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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