Editorial

Cardio-oncology: A new focus for cardiovascular medicine

Worldwide efforts during the past several years have improved cancer-related survival, such that cancer survivorship has tripled from 1970 to 2000. Today, there are more than 12 million cancer survivors in the United States.

As cancer-related survival has improved, an unexpected increase in premature cardiovascular events, including myocardial ischemia and myocardial infarction, stroke, and the development of congestive heart failure, has occurred. Associations have been identified between medications used to treat cancer and CV events. Long-term cancer survivors now represent one of the largest and fastest-growing patient populations at risk for premature CV disease. In fact, increases in CV-related morbidity and mortality now threaten to offset some of the advancements in cancer-related survival.

Currently, however, research initiatives, clinical management and guidelines are lacking, regarding addressing the needs of cancer survivors. In this article, we review the current knowledge related to the etiology, diagnosis, treatment and management of CV disease in cancer survivors and present concepts by which the CV and oncology communities can work together to address the CV needs of cancer survivors.

Chemotherapeutic agents that promote CV injury

As shown in Table 1, multiple agents are linked with CV injury after treatment for cancer. The agents most commonly associated with injury include the anthracyclines such as doxorubicin and alkylating agents such as cyclophosphamide. Recently released agents such as the tyrosine kinase inhibitors have also been associated with CV complications. TKIs regulate multiple cellular functions (including cellular proliferation, differentiation and survival) and are overexpressed in certain malignancies. TKIs include a diverse group of therapies that “down-regulate” malignant cell functions.

Trastuzumab (Herceptin, Genentech) is one of the more frequently described TKIs associated with decrements in left ventricular function. This agent is a monoclonal antibody that targets extracellular HER-2 that can be overexpressed in breast cancer tumors. Interestingly, this receptor is also expressed on developing cardiomyocytes. The association of trastuzumab with CV injury is thought to be related to the drug’s affinity with the HER-2 receptors on cardiomyocytes.

W. Gregory Hundley, MD
W. Gregory Hundley

Sunitinib (Sutent, CPPI CV) is another TKI that has recently been associated with hypertension. Sunitinib inhibits angiogenesis by blocking the activity of VEGF. Although the association of sunitinib with hypertension is not fully understood, it may be related to the reduction in production of vasodilators such as nitrous oxide and prostacyclin, resulting in vasoconstriction and decreased renal excretion of sodium.

Androgen deprivation therapy (ADT) represents another class of cancer treatments that is associated with CV events. Androgen suppression accelerates atherosclerosis and is associated with insulin resistance, obesity, metabolic syndrome, MI and cardiac death. Among 37,443 veterans with prostate cancer, treatment with ADT was associated with diabetes (adjusted HR=1.28); coronary artery disease (adjusted HR=1.19); MI (adjusted HR=1.28); and sudden cardiac death (adjusted HR=1.35). These adverse associations are noteworthy and have prompted initiation of primary CV prevention in many older men scheduled to receive these agents.

Susceptibility and detection

Much of the data relating to susceptibilities to CV injury emanates from the study of children or adults on protocols in which they received anthracycline-based chemotherapeutic agents for the treatment of hematologic malignancies, lymphoma, breast cancer or soft tissue sarcomas. Those more likely to experience anthracycline-related injury are women, those aged older than 65 years or younger than 15 years, and those with pre-existing CV disease or CV risk factors. When compared with their siblings, 14,358 survivors of pediatric cancer followed up to 30 years after their cancer diagnosis were three times more likely to develop a chronic CV event. To date, however, there are relatively few data regarding the factors that increase the risk for a CV event in patients receiving other chemotherapeutic agents.

Currently, intramyocardial biopsies remain the gold standard methodology for identifying myocyte injury as a result of chemotherapy administration. Importantly, however, this technique requires an interventional procedure and is not well-suited for repetitive examinations. For this reason, both radionuclide ventriculography and transthoracic echocardiography (TTE) are widely used to identify marked deteriorations in left ventricular systolic performance when patients receiving chemotherapy or those surviving chemotherapy experience symptoms suggestive of congestive heart failure.

Importantly, these radionuclide ventriculography or traditional 2-D echocardiography methods only identify relatively large deteriorations in left ventricular performance that are most often only associated with clinically overt heart failure. Several recent small studies suggest that quantitative applications regarding MRI or speckle tracking TTE identify the possibility that subclinical markers of CV injury may be identified before more clinically evident overt congestive heart failure ensues. With MRI or TTE, this is achieved through identification of abnormal myocardial tissue characteristics or quantitative assessments of myocardial strain or vascular function. Currently, larger studies are necessary to determine the potential efficacy of these noninvasive modalities for identifying early evidence of myocardial injury that may forecast future CV events.

Prevention and treatment strategies

For those at risk for CV injury before receipt of potentially cardiotoxic chemotherapy, dosing changes either through dose reduction, an alteration of dosing schedules, or a change in the mode of administration of a chemotherapeutic agent have been shown to reduce the risk for CV injury after chemotherapy. Regarding anthracycline toxicity, the cardioprotective agent dexrazoxane (Zinecard, Pfizer) is known to reduce early myocardial injury during anthracycline treatment; however, it remains controversial as to whether this class of agents may reduce the efficacy of cancer treatment.

For those who have experienced CV injury upon receipt of chemotherapy, several small studies have demonstrated potential benefits of angiotensin converting enzyme inhibition or beta-blockade with carvedilol (Coreg, GlaxoSmithKline) to help avert left ventricular remodeling and further deterioration of left ventricular ejection fraction.

Addressing CV concerns in cancer survivors

To date, there are no widespread structured protocols, guidelines or programs that focus on CV care and survivorship-related issues. In 2006, a report from the Institute of Medicine, titled From Cancer Patient to Cancer Survivor: Lost in Transition, sought to raise awareness of the needs of cancer survivors through a series of recommendations. One of the strongest recommendations was to provide comprehensive summary of treatment delivered and detailed plans for undergoing care to patients at the completion of their cancer treatment. Currently, however, there are few organized groups of physicians that are assimilated who can deliver CV care to cancer survivors.

This lack of focus has several major implications. First, although there are specific CV conditions associated with the administration of cancer therapy, there are no standardized definitions for CV disease associated with cancer therapy. Second, most protocols implementing current surveillance measures for cardiac injuries are not coordinated through a central effort; therefore, the selection of outcomes (eg, biomarkers, imaging results) is inconsistent across studies. Third, because CV surveillance is not the primary outcome measure for most of the protocols implemented to test the efficacy of new cancer therapies, there has been inadequate data to provide phenotypic or genotypic characteristics of patients who may be at risk for developing CV disease. Finally, medical societies and health care delivery systems have not determined the optimal pattern for physician surveillance of CV disease in cancer survivors. Thus, although the Institute of Medicine suggests that greater needs and resources should be dedicated toward patient care for most survivors in the US, assessment and treatment of concerns related to CV care are often incomplete.

Table 1

To address these concerns, Albini and colleagues, in an article from the Journal of the National Cancer Institute, have advocated the creation of interdisciplinary “cardio-oncology” teams. The charge of these interdisciplinary teams is to work together to develop research and clinical programs for the purpose of managing CV risk and preventing CV events in both cancer patients and survivors.

The precedence for oncologists and cardiologists to work together exists from the early treatment of CV injury that occurred in the 1960s and 1970s. In these previous decades, those treated with anthracyclines were discovered to have a high risk for clinical CV injury, causing premature CV death and irreversible congestive heart failure. Cardiologists and oncologists at this time worked together to utilize radionuclide ventriculography to identify deteriorations in left ventricular ejection fraction and then develop treatment regimens that would dramatically reduce congestive heart failure and CV death. Today, a somewhat similar intersocietal focus must occur that pulls together the efforts of cardiologists and oncologists for the purpose of assessing CV risk and preventing CV events among cancer survivors.

A call to action

In summary, advances in treatment have reduced cancer-related mortality; however, during the past 10 to 15 years, several investigations have identified an increased incidence of premature CV events in populations of cancer survivors. This increase in CV events threatens to offset some of the gains realized in cancer-related treatments. Today, most of the information related to CV events in survivors is obtained from cancer-directed trials with inconsistent collection of CV-related outcomes. With an increasing number of cancer survivors experiencing an increasing number of CV events, an important opportunity exists to develop research studies focused on cancer survivors to prevent and treat CV events. To address this need, unified efforts are needed between both oncologists and cardiologists working to develop strategies, programs and guidelines to prevent CV events after cancer treatment.

Albini W. Gregory Hundley, MD, is the director of the Cardiovascular Magnetic Resonance Program, and professor, Internal Medicine (Cardiology) and Radiology at Wake Forest School of Medicine in Winston-Salem, N.C. Disclosure: Dr. Hundley reports having received research grants and funding from Bracco Diagnostics and Siemens.

For more information:

  • A. J Natl Cancer Inst. 2010;102:14-25.
  • Cardinale D. J Am Coll Cardiol. 2010;55:213-220.
  • Chaosuwannakit N. J Clin Oncol. 2010;28:166-172.
  • Garcia-Alvarez A. Cardiovasc Hematol Agents Med Chem. 2010;8:11-21.
  • Grenier M. Semin Oncol. 1998;25:72-85.
  • Hewitt M. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, D.C: The National Academies Press; 2006.
  • Keating N. J Natl Cancer Inst. 2010;102:39-46.
  • Mulrooney D. BMJ. 2009;339:b4606.

Worldwide efforts during the past several years have improved cancer-related survival, such that cancer survivorship has tripled from 1970 to 2000. Today, there are more than 12 million cancer survivors in the United States.

As cancer-related survival has improved, an unexpected increase in premature cardiovascular events, including myocardial ischemia and myocardial infarction, stroke, and the development of congestive heart failure, has occurred. Associations have been identified between medications used to treat cancer and CV events. Long-term cancer survivors now represent one of the largest and fastest-growing patient populations at risk for premature CV disease. In fact, increases in CV-related morbidity and mortality now threaten to offset some of the advancements in cancer-related survival.

Currently, however, research initiatives, clinical management and guidelines are lacking, regarding addressing the needs of cancer survivors. In this article, we review the current knowledge related to the etiology, diagnosis, treatment and management of CV disease in cancer survivors and present concepts by which the CV and oncology communities can work together to address the CV needs of cancer survivors.

Chemotherapeutic agents that promote CV injury

As shown in Table 1, multiple agents are linked with CV injury after treatment for cancer. The agents most commonly associated with injury include the anthracyclines such as doxorubicin and alkylating agents such as cyclophosphamide. Recently released agents such as the tyrosine kinase inhibitors have also been associated with CV complications. TKIs regulate multiple cellular functions (including cellular proliferation, differentiation and survival) and are overexpressed in certain malignancies. TKIs include a diverse group of therapies that “down-regulate” malignant cell functions.

Trastuzumab (Herceptin, Genentech) is one of the more frequently described TKIs associated with decrements in left ventricular function. This agent is a monoclonal antibody that targets extracellular HER-2 that can be overexpressed in breast cancer tumors. Interestingly, this receptor is also expressed on developing cardiomyocytes. The association of trastuzumab with CV injury is thought to be related to the drug’s affinity with the HER-2 receptors on cardiomyocytes.

W. Gregory Hundley, MD
W. Gregory Hundley

Sunitinib (Sutent, CPPI CV) is another TKI that has recently been associated with hypertension. Sunitinib inhibits angiogenesis by blocking the activity of VEGF. Although the association of sunitinib with hypertension is not fully understood, it may be related to the reduction in production of vasodilators such as nitrous oxide and prostacyclin, resulting in vasoconstriction and decreased renal excretion of sodium.

Androgen deprivation therapy (ADT) represents another class of cancer treatments that is associated with CV events. Androgen suppression accelerates atherosclerosis and is associated with insulin resistance, obesity, metabolic syndrome, MI and cardiac death. Among 37,443 veterans with prostate cancer, treatment with ADT was associated with diabetes (adjusted HR=1.28); coronary artery disease (adjusted HR=1.19); MI (adjusted HR=1.28); and sudden cardiac death (adjusted HR=1.35). These adverse associations are noteworthy and have prompted initiation of primary CV prevention in many older men scheduled to receive these agents.

Susceptibility and detection

Much of the data relating to susceptibilities to CV injury emanates from the study of children or adults on protocols in which they received anthracycline-based chemotherapeutic agents for the treatment of hematologic malignancies, lymphoma, breast cancer or soft tissue sarcomas. Those more likely to experience anthracycline-related injury are women, those aged older than 65 years or younger than 15 years, and those with pre-existing CV disease or CV risk factors. When compared with their siblings, 14,358 survivors of pediatric cancer followed up to 30 years after their cancer diagnosis were three times more likely to develop a chronic CV event. To date, however, there are relatively few data regarding the factors that increase the risk for a CV event in patients receiving other chemotherapeutic agents.

Currently, intramyocardial biopsies remain the gold standard methodology for identifying myocyte injury as a result of chemotherapy administration. Importantly, however, this technique requires an interventional procedure and is not well-suited for repetitive examinations. For this reason, both radionuclide ventriculography and transthoracic echocardiography (TTE) are widely used to identify marked deteriorations in left ventricular systolic performance when patients receiving chemotherapy or those surviving chemotherapy experience symptoms suggestive of congestive heart failure.

Importantly, these radionuclide ventriculography or traditional 2-D echocardiography methods only identify relatively large deteriorations in left ventricular performance that are most often only associated with clinically overt heart failure. Several recent small studies suggest that quantitative applications regarding MRI or speckle tracking TTE identify the possibility that subclinical markers of CV injury may be identified before more clinically evident overt congestive heart failure ensues. With MRI or TTE, this is achieved through identification of abnormal myocardial tissue characteristics or quantitative assessments of myocardial strain or vascular function. Currently, larger studies are necessary to determine the potential efficacy of these noninvasive modalities for identifying early evidence of myocardial injury that may forecast future CV events.

Prevention and treatment strategies

For those at risk for CV injury before receipt of potentially cardiotoxic chemotherapy, dosing changes either through dose reduction, an alteration of dosing schedules, or a change in the mode of administration of a chemotherapeutic agent have been shown to reduce the risk for CV injury after chemotherapy. Regarding anthracycline toxicity, the cardioprotective agent dexrazoxane (Zinecard, Pfizer) is known to reduce early myocardial injury during anthracycline treatment; however, it remains controversial as to whether this class of agents may reduce the efficacy of cancer treatment.

For those who have experienced CV injury upon receipt of chemotherapy, several small studies have demonstrated potential benefits of angiotensin converting enzyme inhibition or beta-blockade with carvedilol (Coreg, GlaxoSmithKline) to help avert left ventricular remodeling and further deterioration of left ventricular ejection fraction.

Addressing CV concerns in cancer survivors

To date, there are no widespread structured protocols, guidelines or programs that focus on CV care and survivorship-related issues. In 2006, a report from the Institute of Medicine, titled From Cancer Patient to Cancer Survivor: Lost in Transition, sought to raise awareness of the needs of cancer survivors through a series of recommendations. One of the strongest recommendations was to provide comprehensive summary of treatment delivered and detailed plans for undergoing care to patients at the completion of their cancer treatment. Currently, however, there are few organized groups of physicians that are assimilated who can deliver CV care to cancer survivors.

This lack of focus has several major implications. First, although there are specific CV conditions associated with the administration of cancer therapy, there are no standardized definitions for CV disease associated with cancer therapy. Second, most protocols implementing current surveillance measures for cardiac injuries are not coordinated through a central effort; therefore, the selection of outcomes (eg, biomarkers, imaging results) is inconsistent across studies. Third, because CV surveillance is not the primary outcome measure for most of the protocols implemented to test the efficacy of new cancer therapies, there has been inadequate data to provide phenotypic or genotypic characteristics of patients who may be at risk for developing CV disease. Finally, medical societies and health care delivery systems have not determined the optimal pattern for physician surveillance of CV disease in cancer survivors. Thus, although the Institute of Medicine suggests that greater needs and resources should be dedicated toward patient care for most survivors in the US, assessment and treatment of concerns related to CV care are often incomplete.

Table 1

To address these concerns, Albini and colleagues, in an article from the Journal of the National Cancer Institute, have advocated the creation of interdisciplinary “cardio-oncology” teams. The charge of these interdisciplinary teams is to work together to develop research and clinical programs for the purpose of managing CV risk and preventing CV events in both cancer patients and survivors.

The precedence for oncologists and cardiologists to work together exists from the early treatment of CV injury that occurred in the 1960s and 1970s. In these previous decades, those treated with anthracyclines were discovered to have a high risk for clinical CV injury, causing premature CV death and irreversible congestive heart failure. Cardiologists and oncologists at this time worked together to utilize radionuclide ventriculography to identify deteriorations in left ventricular ejection fraction and then develop treatment regimens that would dramatically reduce congestive heart failure and CV death. Today, a somewhat similar intersocietal focus must occur that pulls together the efforts of cardiologists and oncologists for the purpose of assessing CV risk and preventing CV events among cancer survivors.

A call to action

In summary, advances in treatment have reduced cancer-related mortality; however, during the past 10 to 15 years, several investigations have identified an increased incidence of premature CV events in populations of cancer survivors. This increase in CV events threatens to offset some of the gains realized in cancer-related treatments. Today, most of the information related to CV events in survivors is obtained from cancer-directed trials with inconsistent collection of CV-related outcomes. With an increasing number of cancer survivors experiencing an increasing number of CV events, an important opportunity exists to develop research studies focused on cancer survivors to prevent and treat CV events. To address this need, unified efforts are needed between both oncologists and cardiologists working to develop strategies, programs and guidelines to prevent CV events after cancer treatment.

Albini W. Gregory Hundley, MD, is the director of the Cardiovascular Magnetic Resonance Program, and professor, Internal Medicine (Cardiology) and Radiology at Wake Forest School of Medicine in Winston-Salem, N.C. Disclosure: Dr. Hundley reports having received research grants and funding from Bracco Diagnostics and Siemens.

For more information:

  • A. J Natl Cancer Inst. 2010;102:14-25.
  • Cardinale D. J Am Coll Cardiol. 2010;55:213-220.
  • Chaosuwannakit N. J Clin Oncol. 2010;28:166-172.
  • Garcia-Alvarez A. Cardiovasc Hematol Agents Med Chem. 2010;8:11-21.
  • Grenier M. Semin Oncol. 1998;25:72-85.
  • Hewitt M. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, D.C: The National Academies Press; 2006.
  • Keating N. J Natl Cancer Inst. 2010;102:39-46.
  • Mulrooney D. BMJ. 2009;339:b4606.