(1)
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Chapter Overview
Modern therapies for cancer are allowing increasing numbers of patients to enjoy long-term remission or cure of their disease. Unfortunately, the very modalities that help achieve these results cause injury to tissues or organs; these injuries may not be transient and may persist for the duration of survivorship. The heart, as a post-mitotic organ, does not regenerate after injury, and therefore is especially vulnerable to the long-term effects of a variety of treatment strategies for cancer. Although the future holds promise that new initiatives will allow organ or tissue regeneration, at present we must maximize protection of the heart at the time of exposure and minimize sequential stresses that might add to the cardiac burden during the period following the toxic injury. We now understand that cardiac injury may follow some forms of chemotherapy and biologic therapy as well as radiation therapy, and oncologists have learned to protect the heart to minimize the immediate damage. The burden of managing residual cardiac injury, however, migrates to the physician who provides care to cancer survivors, so that the late effects of treatment may be minimized. This chapter explores some of the strategies intended to improve quality of life for patients whose initial treatment for cancer resulted in cardiac injury.
Introduction
The heart is a focus of considerable concern for cancer survivors. Therapeutic interventions that have the potential to be curative can also result in cardiac injury that may be progressive, debilitating, and sometimes fatal. Although primary malignancies of the heart are unusual, and metastatic spread to cardiac tissue suggests advanced and often incurable disease, having a history of cardiac tumors is generally not of special concern during the period of survivorship. Cardiologists have learned to be proactive in minimizing the effects of cancer treatment. In addition, interventions most likely to result in cardiac injury have been identified, as have the patient populations in which the risk of cardiac complications is increased.
Nevertheless, cardiac effects remain a major concern for cancer survivors. Physicians caring for cancer survivors are aware that many of the late cardiac problems associated with cancer treatment become apparent only after years or even decades following the initial injury. The younger a patient is at the time of initial diagnosis or treatment, the more likely late manifestations are to appear during the years of survival. In one retrospective study examining the incidence of congestive heart failure, myocardial infarction, pericardial disease, and valvular disease among adult survivors of childhood cancers, significantly increased incidences of these complications (hazard ratios ranging from 4.8 to 6.3, and even higher hazard ratios when anthracyclines or radiation was used as part of the initial treatment) were found in cancer survivors compared with their siblings (Mulrooney et al. 2009). Additionally, another review focusing on adult survivors of childhood cancer who were treated with anthracyclines or radiation reported a significant dose-related increase in late cardiovascular effects (Tukenova et al. 2010).
Therefore, it is not surprising that the organ most commonly screened for adverse effects in patients prior to, during, and following treatment for cancer is the heart. The heart forms the basis of most preoperative evaluations or evaluations performed prior to starting chemotherapy; evaluation of possible cardiac involvement is sought during the course of many forms of chemotherapy or radiation therapy that encroaches on cardiac structures. Ongoing cardiac surveillance is part of the long-term care program for many cancer survivors, especially those who underwent treatment with anthracyclines, radiation, or a combination of both modalities.
At the present time, much of the effort devoted to cardiac screening or surveillance is intended to quantify, prevent, and recognize treatment-induced contractile dysfunction, often the result of either a loss of myocytes or impairment of their function. However, it should be noted that conditions beyond contractile dysfunction are often observed in this group of patients. In addition to the late effects mentioned above, cardiac dysrhythmia and conduction abnormalities can occur. Furthermore, a broader spectrum of ischemic responses, heart valve abnormalities, and various pericardial syndromes including constriction may be observed.
In addition, damage associated with treatment for cancer may be difficult to detect. The heart has substantial reserves and an astounding ability to compensate for injury, even in the face of substantial injury and loss of individual myocytes. This compensation may make the initial presentation of the injury subtle enough that the injury is undetectable or underestimated. In some cases of cardiac injury, the full extent of the damage becomes evident only months or years after treatment is completed, when compensatory strategies have been exhausted. Even with the introduction of biomarkers and recently developed cardiac ultrasound techniques intended to detect cardiac damage early, currently available tools may be unable to detect or fully estimate cardiac damage at early stages.
This chapter will examine the ways in which the heart is affected by both cancer and its treatment and will provide some guidance in managing, following up, and treating cancer survivors who may have sustained cardiac stress or damage while they had cancer or were undergoing treatment for cancer.
Chemotherapy and Biological Agents
Contractile Dysfunction Following Treatment with Anthracyclines or Other Type I Agents
Concerns regarding contractile dysfunction following some forms of chemotherapy came to the attention of clinicians after the introduction of anthracyclines in the 1960s (Ritchie et al. 1970). Although the mechanisms of injury and the extent of the clinical spectrum of contractile dysfunction have, to a considerable degree, been elucidated, the problem of anthracycline-induced cardiotoxic effects remains one of considerable importance. Anthracyclines are now believed to damage the mitochondria and membrane integrity of myocytes at the time of administration. When the injury exceeds the threshold of reversibility, myocyte death ensues. Anthracyclines, as well as other agents that destroy myocytes, have now been classified as agents that cause type I treatment–related cardiac dysfunction (see Table 19.1). The cardiotoxicity of these agents is related to the cumulative dose; thus type I agents have a limited lifetime allowable cumulative dose. Type I agents are also associated with characteristic structural changes involving cellular organelles.
Table 19.1
Type I and type II treatment-related cardiac dysfunction
Characteristic | Type I treatment-related cardiac dysfunction (example: doxorubicin) | Type II treatment-related cardiac dysfunction (example: trastuzumab) |
|---|---|---|
Primary functional mechanism | Cell death | Cell dysfunction |
Reversibility | Symptoms may respond favorably to treatment, but the underlying cell damage is largely permanent and irreversible | Reversibility established for several agents, although controversy still exists |
Cardiac biopsy results | Typical changes | No typical changes |
Need for long-term treatment when associated with cardiac failure | Yes | Uncertain, especially in instances of full reversibility |
Need for long-term follow-up | Probably prudent | Uncertain |
Loss of cardiac myocytes as a consequence of cardiotoxic chemotherapy with a type I agent affects all cancer survivors treated with such agents, regardless of the survivor’s age at the time of treatment, preexisting cardiac status, or posttreatment cardiac burdens. However, preexisting cardiac stresses may lower the threshold of reversibility, and ongoing cardiac damage may exacerbate the effects of cell loss in patients who are cured of their malignancy. Survivors of cancer who have been treated with type I agents have decreased cardiac reserves, augmenting the effects of subsequent cardiac stress or injury.
However, huge differences exist among patients treated with type I agents, leading to considerable difficulty for clinicians in their attempts to estimate the degree of treatment-related injury. In addition, placing any given patient within a particular risk group may be problematic because preexisting cardiac status is not always easily determined, the degree of damage caused in a particular patient by any identified cumulative dose varies, and the ability of a particular patient to compensate for cardiac damage depends on many factors that cannot always be integrated into the risk estimate. Nevertheless, some principles are well established and can influence decisions regarding surveillance of these patients in the years and decades following their type I agent exposure. Table 19.2 describes some characteristics of patients who have received type I agents and are considered to have a high, intermediate, or low risk of treatment-related cardiac injury. This stratification may help the physician caring for cancer survivors to estimate the need for surveillance, as well as avoid excessive cardiac follow-up that may have limited value.
Table 19.2
Stratification of risk for cardiac injury among patients who have received type I agents
Patient characteristics | Low risk | Intermediate risk | High risk |
|---|---|---|---|
Cumulative dose of doxorubicin or equivalent | <300 mg/m2 | 300–400 mg/m2
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