当代肿瘤治疗的心血管系统副作用

Circulation Journal  Vol.74,  September  2010 Circulation Journal Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp ver the past few decades, cancer treatment has dra- matically evolved. The development and imple- mentation of intensive anticancer treatments have substantially improved the prognosis of cancer patients. Among the recently advanced cancer therapeutic modalities, the progress of chemotherapy is striking. Significant efforts to explore the molecular mechanism of cancer development and progression have recently born fruit, in the so-called ‘molecular-target drugs’. Most are either anti- bodies against cell surface proteins or small molecule protein kinase inhibitors. These drugs bring great promise, especially for advanced or recurrent cancers. Today their application is widening and producing excellent clinical outcomes. Further- more, many new agents are currently under development for clinical use. On the other hand, adverse side-effects of these cytotoxic drugs are inevitable, and some exhibit specific and potentially lethal side-effects on the cardiovascular system. Until recent- ly, we have only needed to consider a few well-described examples of cardiotoxicity of anticancer drugs, such as those accompanying the anthracycline antibiotics. However, now we must also be mindful of the cardiovascular side-effects of these novel molecular-target drugs (Tables 1,2). Both the prevalence and impact of cardiovascular toxicity, including unexpected adverse effects, are expanding. The assessment of a patient’s cardiovascular condition and risks throughout chemotherapy, even years after completion of treatment, has become quite important. With only a few exceptions, most of the molecular mecha- nisms that lead to cardiovascular toxicity during cancer treat- ment remain unclear. Anticancer drugs influence or disrupt pathways that are centrally involved in cell survival, cell growth, inflammatory activation, and angiogenesis (Figure 1), which can spontaneously result in cardiovascular side-effects. Therefore, research on cancer treatment-associated cardiovas- cular side-effects may unveil novel molecular mechanisms that lead to heart failure, atherosclerosis, thrombogenesis, cardiomyocyte regeneration, and arrhythmia. We review the major cardiovascular complications asso- ciated with cancer chemotherapeutic agents that current car- diologists should know about. Oncologists and cardiologists must collaborate closely to further improve the prognosis and quality of life of cancer patients. As was recently proposed, it is time that we explored the interdisciplinary field termed ‘cardioncology’.1 Cytotoxic Agents Anthracycline Antibiotics The most notorious, but best studied, cardiovascular side- effects associated with cancer chemotherapies are those induced by the anthracyclines, including doxorubicin, dauno- rubicin, epirubicin, and idarubicin, which are approved and widely used to treat leukemia and many soft tissue tumors. Anthracyclines accomplish their antitumor activity by inter- calating into nuclear DNA, impairing transcription and cell division, inhibiting topoisomerase II activity, producing reac- tive oxygen species (ROS), and further injuring DNA as well as cell membranes and mitochondria.2 Anthracycline-mediated cardiomyocyte damage is cumu- lative, dose-dependent, and thought to occur through several mechanisms,3–5 but mainly through oxidative stress or free Received July 2, 2010; accepted July 20, 2010; released online August 12, 2010 Department of Clinical Innovative Medicine, Translational Research Center (M.M.), Outpatient Oncology Unit (S.M.), Kyoto University Hospital, Kyoto; and Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai (H.H.), Japan Mailing address: Manabu Minami, MD, PhD, Department of Clinical Innovative Medicine, Translational Research Center, Kyoto Uni- versity Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: mminami@kuhp.kyoto-u.ac.jp ISSN-1346-9843 doi: 10.1253/circj.CJ-10-0632 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp Cardiovascular Side-Effects of Modern Cancer Therapy Manabu Minami, MD, PhD; Shigemi Matsumoto, MD, PhD; Hisanori Horiuchi, MD, PhD Recent advances in chemotherapy have substantially improved the prognosis of cancer patients. However, many  anticancer drugs, especially newly developed ‘molecular-target drugs’, such as the anti-HER2 blocking antibody  and the anti-vascular endothelial growth factor antibody, have serious cardiovascular side-effects such as heart  failure, thromboembolism, severe hypertension and lethal arrhythmia, which interrupt cancer treatment and de- crease the patient’s quality of life. Despite the increasing clinical significance, cardiologists have not been focus- ing enough of their attention on this issue. The major cardiovascular complications associated with anticancer  drugs, and current diagnosis,  treatment and prevention strategies are  reviewed. Close collaborations between  oncologists and cardiologists is necessary to tackle cardiovascular complications and advance cancer treatment.  (Circ J  2010; 74: 1779 – 1786) Key Words:  Cancer; Cardioncology; Cardiotoxicity; Chemotherapy O REVIEW 1780 Circulation Journal  Vol.74,  September  2010 MINAMI M et al. radical formation induced by the electron redox cycling of anthracyclines after binding to DNA.2,6,7 Anthracycline-induced cardiotoxicity can be classified according to the time of onset. Acute or subacute (shortly after intravenous infusion) cardiac side-effects include acute heart failure, myocarditis, myocardial infarction and arrhyth- mias, and were reported to occur in 3.2% of non-Hodgkin’s lymphoma (NHL) patients who were administered doxoru- bicin.8 Arrhythmias, caused by ROS-mediated cardiac ion channel dysfunction, range from atrial fibrillation to supra- Table 1. Antibody-Based Molecular-Target Drugs and Their Cardiovascular Complications Drug Type Target Major cardiovascular complications Trastuzumab (Herceptin) Humanized HER2/neu LV dysfunction, heart failure Cetuximab (Erbitux) Chimeric HER1/EGFR Thromboembolism, hypotension Bevacizumab (Avastin) Humanized VEGF-A Hypertension, thromboembolism, gastrointestinal perforation, LV dysfunction Alemtuzumab (Campath) Humanized CD52 Hypotension Rituximab (Rituxan) Chimeric CD20 Hypotension HER, human epidermal growth factor receptor; LV, left ventricular; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth  factor. Table 2. TKI and Their Cardiovascular Complications Drug Target Major cardiovascular complications Lapatinib (Tykerb) HER1/EGFR, HER2 LV dysfunction Erlotinib (Tarceva) HER1/EGFR * Gefitinib (Iressa) HER1/EGFR * Sunitinib (Sutent) VEGFR1/2/3, KIT, PDGFR, Flt-3, RET, CSF-1 receptor LV dysfunction, hypertension Sorafenib (Nexavar) Raf, VEGFR2/3, KIT, PDGFR, RET Hypertension Imatinib (Glivec) BCR-ABL, KIT, PDGFR LV dysfunction Dasatinib (Sprycel) BCR-ABL, KIT, PDGFR QT prolongation, edema Nilotinib (Tasigna) BCR-ABL, KIT, PDGFR QT prolongation *Severe cardiac toxicity has not yet been reported. TKI, tyrosine kinase inhibitors; VEGFR, VEGF receptors; KIT, stem cell factor receptor; PDGFR, platelet-derived growth-factor receptor; Flt-3,  Fms-like tyrosine kinase 3; RET, receptor tyrosine kinase; CSF-1, colony stimulating factor-1. Other abbreviations see in Table 1. EGF EGF-receptor Ras PI3K Raf ERK Akt PDGF-receptor PDGF Cell growth, Survival, Transformation, Metastasis EGF receptor blocker Raf inhibitor KIT CSF-1 Tyrosine-kinase inhibitor (TKI)Stem Cell Factor P CSF-1 receptor PP P Figure 1.    Targeted treatment of cancers. Molecular-target drugs block signaling pathways involved in tumor growth, apoptosis,  and metastasis. CSF-1, colony stimulating factor-1; EGF, epidermal growth factor; KIT, stem cell factor receptor; PDGF, platelet- derived growth-factor. 1781 Circulation Journal  Vol.74,  September  2010 Cardiovascular Side-Effects of Anticancer Drugs ventricular or ventricular premature contractions, although they rarely become a serious clinical problem.6 The incidence of congestive heart failure (CHF) because of repeated anthracycline administration typically occurs within 1 year after completing the treatment, and depends on the cumulative dose. A report in 19819 showed that the incidence of doxorubicin-induced CHF was 0.14% with total doses less than 400 mg/m2 body surface-area, whereas the incidence increased to 7% at a dose of 550 mg/m2 and to 18% at a dose of 700 mg/m2. In that early study, there was a clear dose-dependent response, with a rapid increase in cardiac toxicity at doses greater than 550 mg/m2. Thus, cumulative doxorubicin doses of 550 mg/m2 are empirically considered a limiting dose to avoid doxorubicin-induced cardiotoxicity. However, in some races, especially the Japanese, there are no data regarding the association of cumulative doses of anthra- cyclines and the incidence of CHF. It is noteworthy that diastolic dysfunction, although gener- ally asymptomatic and subclinical, is considered to start even at cumulative doxorubicin doses of 200 mg/m2.10 Several risk factors that potentially increase cardiac toxicity have been identified, including age, prior chest irradiation, the concur- rent use of other anticancer drugs such as cyclophosphamide, trastuzumab, and taxanes, female sex, preexisting heart dis- ease and hypertension.6 Careful consideration must be given when treating patients with these risk factors, even when the patients have received low cumulative doses of anthracycline. Furthermore, anthracycline-mediated cardiotoxicity is not only a risk for elderly patients but also children. Late-onset cardiac dysfunction, which manifests several years to decades after anthracycline treatment, has been increasingly recognized, often in patients who were treated for cancer during childhood or adolescence. Notably, it was reported that late-onset cardiotoxicity impaired the progno- sis of 5–10% of cancer patients who received anthracycline- containing chemotherapy and would have otherwise been in remission.11 In other reports, late-onset anthracycline-induced left ventricular (LV) dysfunction occurred in 18–65% of patients;12,13 however, the incidence of severely reduced LV function increased with the duration of the follow-up period, suggesting that late-onset cardiac dysfunction is progressive. Aside from heart failure, it is noteworthy that life-threatening arrhythmias and sudden death have been reported in patients more than 15 years after they were treated with anthracy- cline.14 Although the mechanisms of late-onset cardiotoxicity remain unknown, progressive cardiomyocyte injuries that were initially caused by anthracycline must be involved in the delayed decompensation. Cumulative dose, higher rates of anthracycline administration, mediastinal irradiation, and female sex have been identified as risk factors for late-onset cardiac dysfunction. A recent study proposed that impairment of cardiac progenitor cells was involved in the pathogenesis of late-onset cardiotoxicity.15 Currently, early diagnosis and intensive treatment have greatly improved the prognosis of anthracycline-related car- diac failure. Nonetheless, certain patients with late-onset car- diomyopathy require cardiac transplantation.13 Taxanes The taxanes, paclitaxel and docetaxel, are an important new class of anticancer agents that are widely used to treat breast and ovarian cancers. Interestingly, paclitaxel, which is intro- duced via a drug-eluting stent, has shown excellent clinical outcomes regarding in-stent restenosis. Taxanes exhibit their anticancer effects by promoting polymerization of tubulin, leading to the development of dysfunctional microtubules and disturbing cell division. Although most cases of paclitaxel-induced cardiac side- effects are subclinical sinus bradycardia (approximately 30%), paclitaxel may induce heart block with syncope, supraven- tricular or ventricular arrhythmias, and myocardial ischemia through unknown mechanisms.16 Importantly, taxanes poten- tiate anthracycline-induced cardiotoxicity by increasing the plasma levels of doxorubicin, and by promoting the for- mation of the toxic alcoholic metabolite, doxorubicinol, in cardiomyocytes.17 Docetaxel shows less cardiac toxicity than paclitaxel. Fluoropyrimidine 5-fluorouracil (5-FU) is widely used to treat many solid cancers, including gastrointestinal, gynecological, head and neck cancers. Although acute heart failure, arrhythmia, and ECG changes have been associated with 5-FU treatment, the most commonly described and severe cardiac side-effect is myocardial ischemia, which varies clinically from angina to acute myocardial infarction.18 A previous report demon- strated that the frequency of cardiac events, including acute coronary syndromes, was 7.6% and the mortality rate was 2.2% after continuous intravenous infusion of a high dose of 5-FU.18 Patients with a history of coronary artery disease had a higher incidence of ischemic adverse events.19,20 Al- though the etiology is still unknown, it is thought that the cardiovascular toxicity is related to endothelial dysfunction and vasospasm of coronary arteries.19 Capecitabine, an oral prodrug of 5-FU, may also elicit myocardial ischemia and ventricular arrhythmias, although it appears to have less toxicity than 5-FU.20 Cyclophosphamide (CPA) CPA is a common and classical alkylating agent that is wide- ly used in the treatment of leukemia and many solid tumors, including lung, gastrointestinal, gynecological, skin and pha- ryngeal cancers. In addition, CPA is often used for the treat- ment of autoimmune diseases refractory to steroid treatments. Hemorrhagic cystitis is a well-known side-effect of cyclo- phosphamide administration. CPA is generally well tolerated in terms of cardiovascular toxicity. However, high-dose rapid administration (eg, initial therapy for bone marrow transplantation) may induce lethal acute pericarditis and hemorrhagic myocarditis.21 Although the etiology of this complication is not fully understood, direct oxidative cardiac injury has been implicated. Unlike the anthracyclines, the toxicity associated with CPA appears to be related to a single dose and not cumulative doses. In addition, patients who previously received anthracyclines or underwent chest irradiation are more likely to suffer from CPA-induced cardiotoxicity.22 Cisplatin Cisplatin (CDDP) is a chemotherapeutic agent also used widely in the treatment of solid tumors, including lung, gas- trointestinal, urinary, gynecological, head and neck cancers. The mechanism of the anticancer action of CDDP is not fully understood, although binding to DNA leads to the formation of inter- and intrastrand cross-links, resulting in impaired DNA synthesis and replication, further inducing cell death. Dose-limiting side-effects of CDDP include ototoxicity, neurotoxicity, and nephrotoxicity because of renal tubular cell injury. With regard to cardiovascular complications, the 1782 Circulation Journal  Vol.74,  September  2010 MINAMI M et al. pre- and post-therapy hydration that are necessary with CDDP administration to avoid the irreversible nephrotoxicity poten- tially induce hypertension, resulting in exacerbated heart failure. Major cardiac events, including myocardial ischemia, have been reported to occur more than 10 years after CDDP- containing chemotherapy.23 In addition, CDDP-associated nephrotoxicity can lead to a serum electrolyte imbalance, such as hypokalemia or hypomagnesemia, and possibly induce cardiac arrhythmia. Molecular-Target Agents HER2 and HER1/EGFR: Antibodies Trastuzumab Human epidermal growth factor receptor-2 (HER2) is a transmembrane receptor tyrosine kinase also known as ErbB2 or neu. Approximately 20–30% of breast cancers have augmented HER2 expression, which is asso- ciated with a poor prognosis.24 Trastuzumab is an effective humanized IgG1 monoclonal antibody directed against the HER2 protein and is currently used as a central treatment for HER2-positive breast cancers.25 It is well documented that trastuzumab induces LV dys- function and heart failure, especially when it is administered in combination with anthracyclines.26 In the initial phase I–II studies, a single-use of trastuzumab resulted in a low incidence of heart failure or LV dysfunction (4–7% of patients).25,27 However, a subsequent phase III study reported that admin- istering trastuzumab in combination with anthracyclines and CDDP increased the overall incidence of cardiac dysfunc- tion to 27%, with severe heart failure in 16% of patients28 (8% and 3% of patients not treated with trastuzumab experi- enced cardiac dysfunction and heart failure, respectively). Likewise, paclitaxel and trastuzumab combination therapy resulted in symptomatic or asymptomatic cardiac dysfunc- tion in 13% of patients, whereas paclitaxel alone resulted in overall cardiac dysfunction in 1% of patients.28 The mechanisms that lead to these complications are not fully understood, but HER2 signaling is thought to be pivot- ally involved in development of the embryonic heart and in maintaining postnatal cardiac function.29 Although no specific ligand for HER2 has been identified, HER2 can heterodimer- ize with the HER4/ErbB4 receptors in the adult myocardium. Cardiac endothelial cells produce neuregulin-1 (NRG1), which binds to HER4 and promotes its heterodimerization with HER2 (Figure 2). The HER2/HER4 heterodimer subsequent- ly activates various intracellular signaling pathways, includ- ing the PI3-kinase/Akt, MAP kinase, Ras, Raf and Grb2, which are essential for cell growth, glucose uptake, and the turnover of sarcomeric proteins.30 Mice with targeted disrup- tion of the HER2, HER4 or NRG1 genes are embryonically lethal because of aberrant cardiac development.31–33 Addition- ally, ventricular-restricted HER2-deficient conditional mutant mice developed dilated cardiomyopathy, and cardiomyocytes isolated from these mice were susceptible to anthracycline- induced toxicity.34 In addition, immune reaction contributes to trastuzumab-mediated cardiac dysfunction because trastu- zumab facilitates antibody-dependent cell cytotoxicity.35 Aside from prior or concurrent exposure to anthracyclines, other potential risk factors are associated with trastuzumab- related cardiac side effects, including baseline LV ejection fraction (LVEF), prior cardiac diseases, elderly age and pre- vious chest irradiation.36,37 Patients predisposed to cardiovas- cular risk factors (eg, smoking, hypertension, dyslipidemia, diabetes, and obesity) are more likely to experience cardiac HER1 (ErbB1, EGFR) HER2 (ErbB2, neu) HER3 (ErbB3) HER4 (ErbB4) EGF TGF-α amphiregulin HB-EGF Betacellulin epiregulin NRG1 NRG2 NRG3 NGR4 Y Y Y Y Y Y Figure 2.    Epidermal growth factor (EGF) receptor ligands and their binding specificities for human EGF receptor (HER) family.  Binding of these ligands to the HER family results in the formation of homodimers or heterodimers, leading to autophosphoryla- tion of tyrosine residues in the cytoplasm and activation of downstream signaling pathways. Note that the specific ligand for  HER2 is unknown. HER3 lacks a tyrosine kinase domain. TGF, transforming growth factor; HB-EGF, heparin-binding EGF-like  growth factor; NRG, neuregulin. 1783 Circulation Journal  Vol.74,  September  2010 Cardiovascular Side-Effects of Anticancer Drugs damage after trastuzumab treatment.36 Trastuzumab-induced cardiac dysfunction is often revers- ible. In the Herceptin Adjuvant Trial (HERA), withdrawing tr