- Email: [email protected]
Emergence of cardio-oncology
+Model PHARMA-570; No. of Pages 3
ARTICLE IN PRESS
Annales Pharmaceutiques Françaises (2018) xxx, xxx—xxx
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
BRIEF NOTE
Emergence of cardio-oncology Émergence de la cardio-oncologie C.G. Nebigil ∗, L. Désaubry CNRS/Université de Strasbourg, Laboratory of Biomolecules (UMR7203), Sorbonne University—CNRS, Paris, France Received 22 April 2018; accepted 30 June 2018
Summary Cardio-oncology is a new discipline that focuses on understanding, detection, monitoring and treating cardiovascular disease during and after cancer treatment. The development of this emerging field is based on an interdisciplinary collaboration between cardiology and oncology researchers and clinicians. Cardio-oncology aims at identifying how cancer therapies impact cardiovascular homeostasis, particular risk factors, diagnostic biomarkers and novel therapeutic approaches to help to effectively detect, prevent and cure the cardiotoxicity. © 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.
Résumé La cardio-oncologie est une nouvelle discipline qui se concentre sur la compréhension, le dépistage, la surveillance et le traitement des maladies cardiovasculaires pendant et après le traitement du cancer. Le developpement de cette discipline repose sur une collaboration interdisciplinaire entre les chercheurs et les cliniciens en cardiologie et en oncologie. La cardio-oncologie vise à identifier les effets iatrogènes des thérapies anticancéreuses sur l’homéostasie cardiovasculaire, les facteurs de risque particuliers, les biomarqueurs diagnostiques et également à développer des nouvelles approches pour détecter, prévenir et guérir efficacement ces effets secondaires. © 2018 Académie Nationale de Pharmacie. Publié par Elsevier Masson SAS. Tous droits réservés.
∗
Corresponding author. CS 10413, CNRS/Université de Strasbourg, ESBS Pole API, 300, boulevard Sébastien-Brant, 67412 Illkirch, France. E-mail address: [email protected] (C.G. Nebigil).
https://doi.org/10.1016/j.pharma.2018.06.003 0003-4509/© 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Nebigil CG, Désaubry L. Emergence of cardio-oncology. Ann Pharm Fr (2018), https://doi.org/10.1016/j.pharma.2018.06.003
+Model PHARMA-570; No. of Pages 3
ARTICLE IN PRESS
2
C.G. Nebigil, L. Désaubry
Anticancer drug-induced cardiotoxicity is one of the main adverse effects of cancer treatments. It affects the completion of treatment, which can potentially culminate in significant morbidity due to not only the cardiotoxic complications, but also the progression of cancer. Cardiotoxicity, leading to heart failure (HF) is the number two cause of morbidity and mortality among cancer survivors, a group that is growing due to improved cancer treatments. A recent survey of 7 years cancer survivors indicates that 33% of patients died of heart diseases and 51% of cancer. HF as a result of cardiotoxicity can already become evident during treatment, but also up to 20 years after treatment. Delayed HF development is exemplified by long-term childhood cancer survivors having an 11-fold increased chance of developing congestive HF compared with controls [1]. Taking into account the growing cancer survivorship, the clinical significance of anticancer drug-induced cardiotoxicity is gaining importance. Thus, this observation has stimulated the collaboration between oncology and cardiology practitioners and researchers to create a new discipline termed ‘‘cardio-oncology’’. Cardio-oncology teams as well as an increased awareness of potential cardiovascular complications could improve personalized clinical care of cancer patients and advance understanding of underlying mechanisms of cardiovascular morbidity, which help development of new drugs and diagnostic markers (Fig. 1). Early clinical detection of cardiotoxic side effects of both traditional and novel anticancer therapies including tyrosine kinase inhibitors and immunotherapies, as well as an improved understanding of the underlying mechanisms is of high clinical relevance. The initial adverse effects mediated by anticancer drugs to be recognized were cardiotoxicity. The heart is particularly susceptible to chemotherapydependent toxicity for the following reasons; • it is particularly rich in mitochondria (dysfunction of mitochondria activates apoptotic cascade); • heart is highly vascularized and continuously metabolically active (increases exposure to high level of anticancer drugs); • heart has relatively low levels of antioxidant-producing enzymes compared to other tissues (cannot efficiently
Figure 1. Illustration of the main issues in cardio-oncology from basic and translational research to diagnostic, personalized medicine and drug discovery. Illustration des principales questions en cardio-oncologie allant de la recherché fondamentale et translationnelle au diagnostic, la médecine personnalisée et la découverte de médicaments.
protects tissue against reactive oxygen species-mediated oxidative stress); • regeneration of cardiomyocytes is quite limited. Cardiovascular adverse effects can range from myocardial dysfunction, myocarditis, and ischaemia to hypotension, hypertension, as well as QT-interval prolongation, arrhythmias and thromboembolic complications [2]. The incidence of cardiotoxicity depends on a number of different factors related to the therapy such as type of drug, cumulative dose, schedule of administration, route of administration, combination of other cardiotoxic drugs or association with radiotherapy and also to the patient phenotype based on pre-existing cardiovascular risk such as age, presence of classic cardiovascular risk factors, prior exposure to cardiotoxic chemotherapy or radiotherapy. The mechanisms of the underlying cardiovascular toxicity induced by chemotherapeutics can be attributed to two main types of toxicity. The first is on-target toxicity due to inhibition of target kinases expressed in other organ systems such as the heart and vasculature. On-target toxicity typically occurs with imatinib, by inhibition of plateletderived growth factor receptors (PDGFRs), c-kit, Src family members Lck, CSF1R, Cdc2, and discoidin domain receptor (DDR). The second type of toxicity is off-target toxicity. In this case, cardiovascular toxicity occurs because the drug inhibits a signaling pathway that is not among its targets in heart and vasculature. Immunotherapies are an example of off-target toxicity. Novel immunotherapy modality such as monoclonal antibodies targeting immune checkpoints and chimeric antigen receptor therapy (CAR-T therapy) where T-cells are genetically modified to target tumors promotes myocarditis due to cytokine release syndrome (CRS), an acute inflammatory process [3]. Anthracycline are examples of both on-target and off-target toxicity. Anthracyclines belong to a class of chemotherapeutic drugs with a large spectrum of activity from hematological malignancies to solid tumors. The most common initial symptoms of anthracycline-mediated chronic cardiotoxicity is asymptomatic systolic left ventricular dysfunction, leading to progress to congestive HF, if left untreated. The incidence of chronic cardiotoxicity induced by anthracyclines is influenced by a number of factors such as cumulative dose of chemotherapy administered, age of patient, cardiovascular disease history, and prior radiation therapy. It affects from 5 to 65% of patients during anthracyclines treatments. Anthracyclines are also associated with cardiac complications up to a 20% risk of HF after 20 years following a period of treatment with chemotherapy and radiotherapy. Other agents, such as cyclophosphamide, 5fluorouracil and paclitaxel are known to cause cardiac injury as well, albeit at lower rates than anthracyclines [4]. Cardiovascular toxicity can manifest as alteration of the mechanical function of the myocardium and structural and morphological damage of the heart and vasculature. Anthracyclines induce dose-related clinically evident cardiac dysfunction, defined as type I cardiotoxicity, characterized by alteration of the mechanical function of the myocardium, and structural and morphological damage of the heart and vasculature. Anthracyclines produce vacuoles, myofibrillar disarray and necrosis in cardiomyocytes associated with contractile abnormalities. Some cardiac disorders
Please cite this article in press as: Nebigil CG, Désaubry L. Emergence of cardio-oncology. Ann Pharm Fr (2018), https://doi.org/10.1016/j.pharma.2018.06.003
+Model PHARMA-570; No. of Pages 3
ARTICLE IN PRESS
Emergence of cardio-oncology can be initially reversible, but over time the burden of fibrosis and cardiomyocyte death renders the dysfunction irreversible and more refractory to HF therapy. In contrast, type II cardiotoxicity is not associated with ultrastructural change. However it manifests as an asymptomatic decrease in left ventricular ejection fraction (LVEF) and less often by clinical HF. Agents such as trastuzumab and the low molecular weight tyrosine kinase inhibitors (TKIs) for example sunitinib, imatinib, lapatinib and sorafenib cause type II cardiac dysfunction [5]. How can we accurately predict an individual patient’s cardiotoxicity with standard chemotherapy care and determine the risk factors and implementation of prevention/protection strategies are the most challenging question for cardiotoxicity monitoring and management. In 2016, European Research Network on cardiovascular diseases (http://era-cvd2017.u-strasbg.fr/) supported a consortium composed of 6 teams coordinated by a French team, involved in a new drug discovery and signaling pathways in cardio-oncology. The ultimate goal of the cardio-oncology consortium is to reduce the risk of mortality and improve quality of life of patients with anticancer drug-induced cardiotoxicity. Their specific aim is to develop novel effective and safe cardioprotective therapeutics and discover new signaling pathways and biomarkers of cardiotoxicity. Minimizing adverse cardiotoxic effects of anticancer treatments will permit clinicians to fully achieve the benefits of modern cancer therapy. Since cardiotoxicity affects both short-term and long-term quality of life survivorship, researchers and clinicians in Europe and the U.S. recognize that ‘‘quantity’’ of life and ‘‘quality’’ of life are both valued survivor outcomes. However, most European nations have not provided sufficient funding for long-term survivorship research. In contrast, the U.S. has a strong support of government funding for cancer research, including survivorship. Currently, there is no certification for the health professionals in managing cardio-oncology problems in France, but efforts are underway to create a certified training program for the field. First department of clinical cardio-oncology in France has been created in 2015 at Mediterranean Cardio-Oncology Center, Medi-CO, Marseille (http://fr.ap-hm.fr/site/medi-co-center). This center specializes in the management of secondary cardiovascular diseases associated with cancer treatments. The main goal of this center is to reduce the cardiovascular consequences of cancer treatments and improve the survival and quality of life of cancer patients. Their activity is involved in missions
3 of care, research and teaching. In collaboration with other cardiologists, oncologists, and hematologists in the region they provide monitoring management protocols for various cardiovascular toxicities. The ‘‘Cœur & Cancer’’ congress has been organized in 2016 and the first circle of cardiooncology under the Society of French Cardiology has been created in 2018. Institutional and administrative support for the development of adequate infrastructure and the research resources is vital for the continual growth and success of cardiooncology program.
Acknowledgement The publication was made possible by grants from ERA-NET, ERA-CVD, French government managed by Agence nationale de la recherche (ANR) and Centre national de la recherche scientifique.
Disclosure of interest The authors declare that they have no competing interest
References [1] Biasillo G, Cipolla CM, Cardinale D. Cardio-oncology: gaps in knowledge, goals, advances, and educational efforts. Curr Oncol Rep 2017;19:55. [2] Sundararajan S, Kumar A, Poongkunran M, Kannan A, Vogelzang NJ. Cardiovascular adverse effects of targeted antiangiogenic drugs: mechanisms and management. Future Oncol 2016;12:1067—80. [3] Guha A, Armanious M, Fradley MG. Update on cardiooncology: novel cancer therapeutics and associated cardiotoxicities. Trends Cardiovasc Med 2018, http://dx.doi.org/10. 1016/j.tcm.2018.06.001 [pii: S1050-1738(18)30086-0]. [4] Narayan V, Ky B. Common cardiovascular complications of cancer therapy: epidemiology, risk prediction, and prevention. Annu Rev Med 2018;69:97—111. [5] Zamorano JL, Lancellotti P, Rodriguez Mu˜ noz D, Aboyans V, Asteggiano R, Galderisi M, et al. ESC Scientific Document Group 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37: 2768—801.
Please cite this article in press as: Nebigil CG, Désaubry L. Emergence of cardio-oncology. Ann Pharm Fr (2018), https://doi.org/10.1016/j.pharma.2018.06.003
ARTICLE IN PRESS
Annales Pharmaceutiques Françaises (2018) xxx, xxx—xxx
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
BRIEF NOTE
Emergence of cardio-oncology Émergence de la cardio-oncologie C.G. Nebigil ∗, L. Désaubry CNRS/Université de Strasbourg, Laboratory of Biomolecules (UMR7203), Sorbonne University—CNRS, Paris, France Received 22 April 2018; accepted 30 June 2018
Summary Cardio-oncology is a new discipline that focuses on understanding, detection, monitoring and treating cardiovascular disease during and after cancer treatment. The development of this emerging field is based on an interdisciplinary collaboration between cardiology and oncology researchers and clinicians. Cardio-oncology aims at identifying how cancer therapies impact cardiovascular homeostasis, particular risk factors, diagnostic biomarkers and novel therapeutic approaches to help to effectively detect, prevent and cure the cardiotoxicity. © 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.
Résumé La cardio-oncologie est une nouvelle discipline qui se concentre sur la compréhension, le dépistage, la surveillance et le traitement des maladies cardiovasculaires pendant et après le traitement du cancer. Le developpement de cette discipline repose sur une collaboration interdisciplinaire entre les chercheurs et les cliniciens en cardiologie et en oncologie. La cardio-oncologie vise à identifier les effets iatrogènes des thérapies anticancéreuses sur l’homéostasie cardiovasculaire, les facteurs de risque particuliers, les biomarqueurs diagnostiques et également à développer des nouvelles approches pour détecter, prévenir et guérir efficacement ces effets secondaires. © 2018 Académie Nationale de Pharmacie. Publié par Elsevier Masson SAS. Tous droits réservés.
∗
Corresponding author. CS 10413, CNRS/Université de Strasbourg, ESBS Pole API, 300, boulevard Sébastien-Brant, 67412 Illkirch, France. E-mail address: [email protected] (C.G. Nebigil).
https://doi.org/10.1016/j.pharma.2018.06.003 0003-4509/© 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Nebigil CG, Désaubry L. Emergence of cardio-oncology. Ann Pharm Fr (2018), https://doi.org/10.1016/j.pharma.2018.06.003
+Model PHARMA-570; No. of Pages 3
ARTICLE IN PRESS
2
C.G. Nebigil, L. Désaubry
Anticancer drug-induced cardiotoxicity is one of the main adverse effects of cancer treatments. It affects the completion of treatment, which can potentially culminate in significant morbidity due to not only the cardiotoxic complications, but also the progression of cancer. Cardiotoxicity, leading to heart failure (HF) is the number two cause of morbidity and mortality among cancer survivors, a group that is growing due to improved cancer treatments. A recent survey of 7 years cancer survivors indicates that 33% of patients died of heart diseases and 51% of cancer. HF as a result of cardiotoxicity can already become evident during treatment, but also up to 20 years after treatment. Delayed HF development is exemplified by long-term childhood cancer survivors having an 11-fold increased chance of developing congestive HF compared with controls [1]. Taking into account the growing cancer survivorship, the clinical significance of anticancer drug-induced cardiotoxicity is gaining importance. Thus, this observation has stimulated the collaboration between oncology and cardiology practitioners and researchers to create a new discipline termed ‘‘cardio-oncology’’. Cardio-oncology teams as well as an increased awareness of potential cardiovascular complications could improve personalized clinical care of cancer patients and advance understanding of underlying mechanisms of cardiovascular morbidity, which help development of new drugs and diagnostic markers (Fig. 1). Early clinical detection of cardiotoxic side effects of both traditional and novel anticancer therapies including tyrosine kinase inhibitors and immunotherapies, as well as an improved understanding of the underlying mechanisms is of high clinical relevance. The initial adverse effects mediated by anticancer drugs to be recognized were cardiotoxicity. The heart is particularly susceptible to chemotherapydependent toxicity for the following reasons; • it is particularly rich in mitochondria (dysfunction of mitochondria activates apoptotic cascade); • heart is highly vascularized and continuously metabolically active (increases exposure to high level of anticancer drugs); • heart has relatively low levels of antioxidant-producing enzymes compared to other tissues (cannot efficiently
Figure 1. Illustration of the main issues in cardio-oncology from basic and translational research to diagnostic, personalized medicine and drug discovery. Illustration des principales questions en cardio-oncologie allant de la recherché fondamentale et translationnelle au diagnostic, la médecine personnalisée et la découverte de médicaments.
protects tissue against reactive oxygen species-mediated oxidative stress); • regeneration of cardiomyocytes is quite limited. Cardiovascular adverse effects can range from myocardial dysfunction, myocarditis, and ischaemia to hypotension, hypertension, as well as QT-interval prolongation, arrhythmias and thromboembolic complications [2]. The incidence of cardiotoxicity depends on a number of different factors related to the therapy such as type of drug, cumulative dose, schedule of administration, route of administration, combination of other cardiotoxic drugs or association with radiotherapy and also to the patient phenotype based on pre-existing cardiovascular risk such as age, presence of classic cardiovascular risk factors, prior exposure to cardiotoxic chemotherapy or radiotherapy. The mechanisms of the underlying cardiovascular toxicity induced by chemotherapeutics can be attributed to two main types of toxicity. The first is on-target toxicity due to inhibition of target kinases expressed in other organ systems such as the heart and vasculature. On-target toxicity typically occurs with imatinib, by inhibition of plateletderived growth factor receptors (PDGFRs), c-kit, Src family members Lck, CSF1R, Cdc2, and discoidin domain receptor (DDR). The second type of toxicity is off-target toxicity. In this case, cardiovascular toxicity occurs because the drug inhibits a signaling pathway that is not among its targets in heart and vasculature. Immunotherapies are an example of off-target toxicity. Novel immunotherapy modality such as monoclonal antibodies targeting immune checkpoints and chimeric antigen receptor therapy (CAR-T therapy) where T-cells are genetically modified to target tumors promotes myocarditis due to cytokine release syndrome (CRS), an acute inflammatory process [3]. Anthracycline are examples of both on-target and off-target toxicity. Anthracyclines belong to a class of chemotherapeutic drugs with a large spectrum of activity from hematological malignancies to solid tumors. The most common initial symptoms of anthracycline-mediated chronic cardiotoxicity is asymptomatic systolic left ventricular dysfunction, leading to progress to congestive HF, if left untreated. The incidence of chronic cardiotoxicity induced by anthracyclines is influenced by a number of factors such as cumulative dose of chemotherapy administered, age of patient, cardiovascular disease history, and prior radiation therapy. It affects from 5 to 65% of patients during anthracyclines treatments. Anthracyclines are also associated with cardiac complications up to a 20% risk of HF after 20 years following a period of treatment with chemotherapy and radiotherapy. Other agents, such as cyclophosphamide, 5fluorouracil and paclitaxel are known to cause cardiac injury as well, albeit at lower rates than anthracyclines [4]. Cardiovascular toxicity can manifest as alteration of the mechanical function of the myocardium and structural and morphological damage of the heart and vasculature. Anthracyclines induce dose-related clinically evident cardiac dysfunction, defined as type I cardiotoxicity, characterized by alteration of the mechanical function of the myocardium, and structural and morphological damage of the heart and vasculature. Anthracyclines produce vacuoles, myofibrillar disarray and necrosis in cardiomyocytes associated with contractile abnormalities. Some cardiac disorders
Please cite this article in press as: Nebigil CG, Désaubry L. Emergence of cardio-oncology. Ann Pharm Fr (2018), https://doi.org/10.1016/j.pharma.2018.06.003
+Model PHARMA-570; No. of Pages 3
ARTICLE IN PRESS
Emergence of cardio-oncology can be initially reversible, but over time the burden of fibrosis and cardiomyocyte death renders the dysfunction irreversible and more refractory to HF therapy. In contrast, type II cardiotoxicity is not associated with ultrastructural change. However it manifests as an asymptomatic decrease in left ventricular ejection fraction (LVEF) and less often by clinical HF. Agents such as trastuzumab and the low molecular weight tyrosine kinase inhibitors (TKIs) for example sunitinib, imatinib, lapatinib and sorafenib cause type II cardiac dysfunction [5]. How can we accurately predict an individual patient’s cardiotoxicity with standard chemotherapy care and determine the risk factors and implementation of prevention/protection strategies are the most challenging question for cardiotoxicity monitoring and management. In 2016, European Research Network on cardiovascular diseases (http://era-cvd2017.u-strasbg.fr/) supported a consortium composed of 6 teams coordinated by a French team, involved in a new drug discovery and signaling pathways in cardio-oncology. The ultimate goal of the cardio-oncology consortium is to reduce the risk of mortality and improve quality of life of patients with anticancer drug-induced cardiotoxicity. Their specific aim is to develop novel effective and safe cardioprotective therapeutics and discover new signaling pathways and biomarkers of cardiotoxicity. Minimizing adverse cardiotoxic effects of anticancer treatments will permit clinicians to fully achieve the benefits of modern cancer therapy. Since cardiotoxicity affects both short-term and long-term quality of life survivorship, researchers and clinicians in Europe and the U.S. recognize that ‘‘quantity’’ of life and ‘‘quality’’ of life are both valued survivor outcomes. However, most European nations have not provided sufficient funding for long-term survivorship research. In contrast, the U.S. has a strong support of government funding for cancer research, including survivorship. Currently, there is no certification for the health professionals in managing cardio-oncology problems in France, but efforts are underway to create a certified training program for the field. First department of clinical cardio-oncology in France has been created in 2015 at Mediterranean Cardio-Oncology Center, Medi-CO, Marseille (http://fr.ap-hm.fr/site/medi-co-center). This center specializes in the management of secondary cardiovascular diseases associated with cancer treatments. The main goal of this center is to reduce the cardiovascular consequences of cancer treatments and improve the survival and quality of life of cancer patients. Their activity is involved in missions
3 of care, research and teaching. In collaboration with other cardiologists, oncologists, and hematologists in the region they provide monitoring management protocols for various cardiovascular toxicities. The ‘‘Cœur & Cancer’’ congress has been organized in 2016 and the first circle of cardiooncology under the Society of French Cardiology has been created in 2018. Institutional and administrative support for the development of adequate infrastructure and the research resources is vital for the continual growth and success of cardiooncology program.
Acknowledgement The publication was made possible by grants from ERA-NET, ERA-CVD, French government managed by Agence nationale de la recherche (ANR) and Centre national de la recherche scientifique.
Disclosure of interest The authors declare that they have no competing interest
References [1] Biasillo G, Cipolla CM, Cardinale D. Cardio-oncology: gaps in knowledge, goals, advances, and educational efforts. Curr Oncol Rep 2017;19:55. [2] Sundararajan S, Kumar A, Poongkunran M, Kannan A, Vogelzang NJ. Cardiovascular adverse effects of targeted antiangiogenic drugs: mechanisms and management. Future Oncol 2016;12:1067—80. [3] Guha A, Armanious M, Fradley MG. Update on cardiooncology: novel cancer therapeutics and associated cardiotoxicities. Trends Cardiovasc Med 2018, http://dx.doi.org/10. 1016/j.tcm.2018.06.001 [pii: S1050-1738(18)30086-0]. [4] Narayan V, Ky B. Common cardiovascular complications of cancer therapy: epidemiology, risk prediction, and prevention. Annu Rev Med 2018;69:97—111. [5] Zamorano JL, Lancellotti P, Rodriguez Mu˜ noz D, Aboyans V, Asteggiano R, Galderisi M, et al. ESC Scientific Document Group 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37: 2768—801.
Please cite this article in press as: Nebigil CG, Désaubry L. Emergence of cardio-oncology. Ann Pharm Fr (2018), https://doi.org/10.1016/j.pharma.2018.06.003