Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section G – Complications of Therapy

Chapter 63 – Cardiac Effects of Cancer Therapy

James L. Speyer,Boris Kobrinsky,
Michael S. Ewer

SUMMARY OF KEY POINTS

Incidence

Cardiomyopathy/Congestive Heart Failure

  

   

Anthracyclines: 5% to 20% of patients receiving cumulative doxorubicin more than 450 mg/m2, higher in children

  

   

Other antineoplastics (mitoxantrone, cyclophosphamide): less than 2%

  

   

Trastuzumab

  

   

Imatinib

  

   

Lapatinib

  

   

Sunitinib

  

   

Radiation therapy: common 5 to 20 years after single anteroposterior port

Arrhythmias

  

   

Paclitaxel: less than 1%

  

   

Dihydroazacytidine

  

   

Interleukin-2, interleukin-6

  

   

Interleukin-11

  

   

Rituximab

  

   

Arsenic trioxide

Myocardial Ischemia

  

   

Radiation therapy

  

   

5-Fluorouracil (5-FU): 1% to 4.5% with infusion schedules

  

   

Capecitabine

Pericardial Disease

  

   

Radiation therapy: effusions in 6% to 30% of patients receiving radiation therapy to the chest, constriction in 2% of patients receiving radiation therapy to the chest with current techniques

  

   

Cardiac tamponade

  

   

Busulfan

Fluid Retention

  

   

Docetaxel, interleukins, interferons, tumor necrosis factor, cytokines, granulocyte-macrophage colony-stimulating factor, monoclonal antibody (CD20)

  

   

Dasatinib

  

   

All-trans retinoic acid

Hypertension

  

   

Bevacizumab

Hypotension

  

   

Rituximab

  

   

All-trans retinoic acid

  

   

Bortezomib

  

   

Paclitaxel

  

   

INF

  

   

Denileukin diftitox

Endocardial Fibrosis

  

   

Busulfan

Etiology of Complications

  

   

Anthracycline-induced cardiomyopathy

  

   

Her2 signaling pathway and decreased repair

  

   

Radiation-induced cardiomyopathy

  

   

Radiation-induced myocardial ischemia

  

   

Decreased systemic vascular resistance

Diagnosis

  

   

Clinical cardiac symptoms—New York Heart Association Classification

  

   

Hemodynamics—Bristow Staging Score

  

   

Radionuclide scans—serial scans including baseline

  

   

Endomyocardial biopsy—Billingham Histopathologic Scoring System

  

   

Doppler echocardiography—pericardial effusion/constriction, left ventricular systolic/diastolic dysfunction

  

   

Troponin

  

   

Natriuretic peptide

Treatment

Cardiomyopathy/Congestive Heart Failure

  

   

Sodium and fluid restriction

  

   

Diuretics

  

   

Afterload reduction (angiotensin-converting enzyme inhibitors)

  

   

Angiotensin receptor blocking agents

  

   

Beta blockers

  

   

Discontinue offending agent

Risk Reduction with Anthracyclines

  

   

Anthracyclines: limit dose (e.g., doxorubicin: <450 mg/m2); use less toxic analogs

  

   

Alteration of dose schedule

  

   

Unique delivery systems (e.g., liposomes)

  

   

Pegylated liposomal doxorubicin

  

   

Blocking agents (dexrazoxane: ICRF-187, ADR 529) (Zinecard)

Radiation-Induced Pericardial Disease

  

   

Acute pericarditis: nonsteroidal anti-inflammatory drugs, steroids

  

   

Constriction: pericardiectomy

INTRODUCTION

The cardiac side effects of cancer therapies include the entire breadth of cardiac pathology. They provide a considerable challenge to the clinician because they produce signs and symptoms of disease that are not specific to treatment and their differential diagnosis therefore includes a broad spectrum of other etiologies. The sequelae of the tumors being treated, underlying cardiac disease, and effects of nononcologic interventions can affect the heart in ways that often cannot be distinguished clinically from the cardiac effects of cancer treatment. These factors make the diagnosis, assessment, and clinical course of the cardiac effects of cancer therapy especially challenging. Despite these considerations, it is clear that dysrhythmias, ischemia, congestive heart failure (CHF), peripheral vascular disease, and pericardial disease can be caused by a variety of cancer therapies and the various combinations of agents and modalities that are used in the treatment of malignancy.

A variety of approaches can be used to effectively evaluate patients with these side effects. The patient with cancer who presents with cardiac problems can be approached by considering all known side effects associated with the therapy or therapies that he or she is receiving or has received in the past. Alternatively, the entire spectrum of treatment-related, as well as nontreatment-related, causes of the patient's cardiac presentation can be considered. Because the latter approach is closer to the usual clinical process of differential diagnosis, this chapter is organized in that manner. However, to consider side effects by therapeutic agent and modality, a summary is organized according to the effects of specific agents ( Table 63-1 ).


Table 63-1   -- Cardiovascular Complications of Cancer Therapies

CHEMOTHERAPY DRUGS

BIOLOGIC RESPONSE MODIFIERS

Therapy

Complications

Therapy

Complications

Anthracyclines (e.g., doxorubicin)

Cardiomyopathy

IFN-α

Hypotension

 

CHF[*]

 

Tachycardia

 

Dysrhythmias

IFN-β

Hypotension

Epirubicin

Pericardial effusion

TFN-γ

Hypotension

Anthrapyrazoles

Cardiomyopathy

Interleukin-1α

Hypotension

 

CHF

Interleukin-2

CHF

Mitoxantrone

Cardiomyopathy

 

Hypotension

 

CHF[*]

 

Dysrhythmias

Cyclophosphamide

CHF

 

Ischemia

 

Hemorrhagic myocarditis[*]

Interleukin-4

Myocarditis

 

Pericardial effusion

Interleukin-6

Dysrhythmias

Ifosfamide

CHF

Interleukin-11

Atrial dysrhythmias

5-Fluorouracil

Myocardial ischemia[*]

TNF

Hypotension[*]

 

Cerebrovascular ischemia

GM-CSF

Hypotension

Vinca alkaloids

Angina

 

Pericardial effusion

 

Raynaud phenomenon

Monoclonal Ab to CD20

Hypotension

Dihydro-5-azacytidine

Dysrhythmias

 

Angina

 

Pericardial effusion

 

Dysrhythmias

Paclitaxel (Taxol)

Dysrhythmias

Radiation therapy

CHF

 

ECG changes

 

Coronary artery disease[*]

 

Ischemia

 

Pericarditis[*]

Docetaxel (Taxotere)

Fluid retention

 

Pericardial effusion

Cisplatin

Raynaud phenomenon[*]

 

Constriction[*]

Bleomycin

Raynaud phenomenon[*]

 

 

Taxol + doxorubicin

Cardiomyopathy

 

 

Thalidomide in combination

Thromboembolic events

 

 

Trastuzumab

CHF

 

 

Lapatinib

CHF

 

 

Imatinib

CHF

 

 

Dasatinib

Fluid retention

 

 

 

Dysrhythmias

 

 

Sunitinib

Decrease in LVEF

 

 

Arsenic trioxide

Dysrhythmias

 

 

All-trans retinoic acid

Fluid retention, hypotension

 

 

Capecitabine

Myocardial ischemia

 

 

Rituximab

Dysrhythmias

 

 

Bortezomib

 

 

 

Ab, antibody; CHF, congestive heart failure; ECG, electrocardiographic; IFN, interferon; GM-CSF, granulocyte macrophage colony-stimulating factor; TNF, tumor necrosis factor.

 

*

Significant effect.

 

In the cancer patient, a complex of interactions result from specific agents or modalities, causing damage through different pathophysiologic mechanisms, such as ischemia, free radical myocardial damage, radiation damage, alterations in conduction, and other factors that increase myocardial stress such as increased work, wall stress, and underlying ischemia. These may be modulated by cardiac repair mechanisms or strategies to reduce stress on the heart. Drugs that reduce cardiac repair or add to cardiac work or wall stress may in turn increase cardiac toxicity and worsen a patient's condition. In the case of some newer anticancer treatments, these drugs may cause additive or synergistic damage. Ewer and Lippman[1] have proposed a classification schema that indicates different types of myocyte damage leading to CHF with different pathophysiologic mechanisms and different clinical courses. A schematic model of these interactions as well as other sources of cardiac stress depicts multiple sources of cardiac stress and repair ( Fig. 63-1 ).

 
 

Figure 63-1  Mechanisms of cardiac toxicity and repair with proposed modified classification system. [1] [78]

 

 

Finally, as with all potentially negative effects of treatment, the clinician needs to balance the potential risk or negative impact on the patient with the potential benefit. Simply withholding treatment may eliminate the risk of a side effect but deprive the patient of a potentially beneficial therapy. At times, this may be the correct approach. At other times, giving treatment with judicious monitoring and appropriate toxicity reduction may on balance benefit the patient more.

CONGESTIVE HEART FAILURE

Previously, the major emphasis in drug-induced cardiac toxicity has been on anthracycline-induced damage because of the widespread use of these drugs, their unique mechanism of action and pathologic appearance, and clinically relevant toxicity. While anthracyclines remain an important part of any discussion of cardiac toxicity, the recent introduction of many new agents with activity, especially in cell-signaling pathways, makes consideration of treatment-related cardiac effects more complex and clinically important. The mechanisms by which these drugs inhibit tumor cell growth may also be involved in the normal response to stress by cardiac myocytes and can result in clinical toxicity alone or in combination with other drugs or sources of cardiac stress (e.g., traztuzumab, lapatinib, imatinib). Others may have direct cardiac toxicity.

Anthracyclines

Chemotherapy that incorporates an anthracycline antibiotic is a significant cause of CHF in cancer patients who are treated with these agents ( Table 63-2 ). The anthracyclines are of special interest, in part because CHF resulting from these agents can progress to death. We now are able, in large part, to prevent the potentially deadly aspects of CHF from anthracycline use. Most information relating to anthracycline-induced cardiomyopathy is derived from studies with doxorubicin and, to a lesser extent, with daunorubicin. However, other clinically available drugs of this class also have been associated with clinically indistinguishable cardiotoxic effects.


Table 63-2   -- Anthracyclines and/or Anthraquinolones and Cardiotoxicity Associated with Cardiomyopathy in Clinical Use

Doxorubicin (Adriamycin)

Daunorubicin (Daunomycin)

4’Epidoxorubicin (Epiadriamycin/Epirubicin)

4’Deoxydoxorubicin (Esorubicin)

Demethoxydaunorubicin (Idarubicin)

Pegylated doxorubicin (Doxil)

Liposomal daunorubicin (Daunosome)

Mitoxantrone (anthracycline analog)

TLC D99 (Myocet)

 

 

Cardiac biopsy specimens have demonstrated that the dose-related cardiomyopathy that is associated with anthracyclines is biventricular. Retrospective studies indicate that the incidence of clinically recognizable congestive failure with doxorubicin is 7% to 15% in patients who have received a cumulative dose greater than 450 to 500 mg/m2 without cardioprotection ( Fig. 63-2 ). [2] [3] Above this dose the incidence of clinical CHF rises more steeply. (Cumulative cardiotoxic doses associated with the use of other anthracyclines vary, but the shape of the curve that plots cumulative dose against the likelihood of CHF is similar for all anthracyclines that have been studied.) Caution must be exercised in evaluating patients who are receiving anthracyclines, because this cardiomyopathy is variable, and instances of CHF have been observed at lower cumulative doses.[4] The actual incidence of clinical CHF may be higher than was reported in retrospective trials. [5] [6] Prospective clinical trials suggest that when patients are observed closely, the number who develop early signs of CHF at cumulative doses of 450 mg/m2 may exceed 25%. The cardiotoxic effects of anthracyclines probably start with the first dose. Each subsequent administration constitutes a sequential stress superimposed on existing cardiac injury that may have resulted from prior doses of anthracyclines or from other causes. In addition, nonanthracycline-related stress or damage occurring months or years later finds the heart with pre-existing damage and adds a cumulative burden or sequential stress.[7] Other chemotherapy drugs (e.g., trastuzumab) that may have a collateral effect of decreasing cardiac repair mechanisms can increase anthracycline toxicity (see later discussion).

 
 

Figure 63-2  Incidence of clinical congestive heart failure according to cumulative dose of doxorubicin.  (Data from Swain SM et al, Personal communication. Studies 88001, 88002, 88006; von Hoff et al, 1979.)

 

 

 

Factors associated with an increased risk of anthracycline-induced chronic cardiomyopathy are derived from retrospective studies in adults.[2] They include age greater than 70 years, exposure to ionizing radiation to the chest wall, and pre-existing cardiac disease or risk factors. Prior cardiac risk factors include active CHF, history of myocardial infarction within the preceding year, hypertension, aortic stenosis, diabetes mellitus, and prior exposure to anthracyclines. The relative contributions of each of these factors are not well defined, and when an individual patient has more than one risk factor, the damage can be increased considerably. One possible common denominator among these entities is increased wall stress; any condition that results in increased wall stress warrants heightened scrutiny and efforts to mitigate the cardiotoxic effects of anthracyclines. Children are a subset of patients who are at increased risk for developing anthracycline cardiac toxicity with a different clinical course and some difference in mechanism (see later discussion).

The natural history of the cardiomyopathy from anthracycline use varies. In some patients, it worsens despite maximal medical therapy and can lead inexorably to death. Other patients are left with permanent reduction in left ventricular ejection fraction (LVEF) and persistent symptoms of CHF. Still others can experience gradual improvement in symptoms and LVEF,[8] perhaps owing in part to compensation and myocardial remodeling.

Pathophysiology

Anthracycline-induced cardiomyopathy is the result of a series of repeated chemical injuries to the myocardium (possibly with some recovery) that gradually impair cellular defenses, resulting in cell damage with decreased contractility and, eventually, cell death. This is consistent with the gradual onset, variability of course, risk factors for increased susceptibility, and laboratory and pathologic findings of the cardiomyopathy that results from use of these drugs.

The common mechanism for anthracycline cardiomyopathy appears to be via free radical damage. Reduction of the quinone groups on the B ring of the anthracene structure ( Fig. 63-3 ) results in a semiquinone radical before further reduction to the alcohol (e.g., doxorubicinol). Interaction with oxygen yields free radical oxygen (O2*). Further reaction of the semiquinone with H2O2 yields the OH-radical. These reactions can proceed in either an iron-independent or iron-dependent fashion.[9]

 
 

Figure 63-3  Redox cycling of doxorubicin by flavin-centered reductases.  (From Muggia FM, Green MD, Speyer JL [eds]: Cancer Treatment and the Heart. Baltimore, Johns Hopkins University Press, 1992, p 12.)

 

 

 

Formation of an Fe3+-doxorubicin complex can catalyze these reactions, greatly enhancing free radical generation. An Fe3+-doxorubicin DNA complex has been demonstrated, which results in increased cell destruction. Free radicals can cause damage at a variety of intracellular sites, including the nuclear envelope, cell membrane, mitochondria, DNA, and sarcoplasmic reticulum. [9] [10] In the myocyte, damage to the sarcoplasmic reticulum produces a decrease in bound calcium, which results in decreased contractility by its action on the actin-myosin complex. Free Ca2+ also may activate proteases within the heart, causing myofibrillar damage.

Anthracycline-induced free radical damage is not confined to the myocardium. It may indeed play some role in tumor cell killing, although this is primarily thought to be related to other mechanisms (e.g., DNA intercalation, inhibition of topoisomerase II).

The susceptibility of myocardial cells to free radicals may be explained in part by differences in cellular defenses. Of the primary cellular enzymatic defenses against free radicals—superoxide dismutase, catalase and glutathione peroxidase—only superoxide dismutase is unaffected by doxorubicin. In some mammalian systems, myocytes contain very low catalase compared to other cells, such as liver cells.[11] Furthermore, doxorubicin can decrease cellular glutathione peroxidase. The complete translation of the observations from the rodent system to humans is not clear.

In clinical practice, the anthracyclines appear to have a mechanism of activity similar to that just described. The mechanisms do not, however, fully explain the cardiac effects of the related anthracene compounds (e.g., mitoxantrone). In isolated myocyte models, specific inhibitory agents (dexrazoxane) inhibit anthracycline-induced cardiac damage but not that of mitoxantrone, suggesting that some other mechanism for cardiac toxicity also might exist.[12] In a spontaneously hypertensive rat model, though, dexrazoxane inhibits both doxorubicin and mitoxantrone-induced cardiac toxicity.[13] Some investigators have suggested that in addition to the preceding mechanism, cardiac damage in children is due at least in part to interference with cell growth.[14]

Diagnosis

Patients may present with any or all symptoms of CHF, including decreased exercise tolerance, dyspnea, or signs of pulmonary and circulatory congestion. In our experience, sinus tachycardia and an inability to return promptly to basal cardiac rate after exertion in an otherwise oncologically stable patient are the earliest sign of myocardial toxicity and usually predate more classic symptoms of heart failure. These can be graded by the well-established system for grading CHF.[15] A system of staging anthracycline-induced hemodynamic changes in humans was developed by Bristow.[16] Severity is most frequently indicated by LVEF (absolute value and decrease during treatment) and clinical findings, often using the New York Heart Association classification of CHF.

Determination of LVEF by either cardiac ultrasound or gated radionuclide scanning techniques is used to assess anthracycline cardiac toxicity. However, changes in systolic function often are seen in cancer patients, and they might not be related to anthracycline-associated damage. Such changes may occur as a consequence of anemia, the extent of tumor burden, and a variety of metabolic aberrations that might or might not be related to the malignancy or its treatment. One way to monitor patients with echocardiography or nuclear imaging is to obtain a baseline study prior to therapy and then obtain values at intervals as the cumulative dose increases. At high cumulative doses, it might be desirable to make more frequent observations. Scans are examined for sequential changes in wall motion as well as LVEF. Any decrease in LVEF, including those that remain within the “normal” range as well as those that decrease to a clearly abnormal value, could indicate anthracycline damage.[17] Careful monitoring with multiple gated acquisition (MUGA) scans may permit treatment with greater cumulative doses of doxorubicin than an empiric stopping dose of 450 to 500 mg/m2. [3] [5] [17] [18] Serial determinations might, however, result in premature abandonment of an important therapy because of false-positive results on an ultrasound or MUGA scan. It is important to bear in mind that the likelihood of CHF follows an exponential curve, that early toxicity can be difficult to quantify, and that an additional two or three cycles of chemotherapy may expose patients to life-threatening cumulative dosages. Decreases in the absolute value of LVEF by 10% to 20% or to less than the lower limit of normal for the laboratory may warrant discontinuation of therapy. The key is that a decrease in LVEF usually precedes the development of clinical CHF and that termination of drug therapy might stop the progression of the biochemical process before clinical symptoms became apparent. Algorithmic validation of this approach has been published and supports this approach, but it is not fail-safe. When exceeding of recommended cumulative dosages can be anticipated, cardioprotective strategies are clearly appropriate.

Although MUGA scans have been used in most adult investigational studies and for clinical follow-up, Doppler echocardiography is also a useful tool for both preanthracycline evaluation of the heart (allowing assessment of underlying valvular and pericardial pathology as well as myocardial systolic and diastolic function) and clinical follow-up during treatment. Newer computer-assisted echocardiographic technologies, including automated border detection-derived quantification of cardiac volumes and LVEF, could make nuclear quantification modalities (which require radioisotopes) obsolete in patients whose hearts can be imaged ultrasonically.[19] Doppler evaluation of diastolic parameters, including rates of isovolemic relaxation and rapid filling, can be useful in the early detection of anthracycline-induced myocardial dysfunction.[20] Echocardiography has been used extensively in children, in whom the shorter periods of time needed to acquire data are helpful. In patients with cardiac dysrhythmias, the rhythm disturbance can interfere with cardiac gating, and echocardiography offers advantages. Patients who have received radiation to the left side of the chest can be difficult to study with cardiac ultrasound and often are better candidates for nuclear imaging.[21]

Myoscint scans may complement MUGA scans. In trials using Myoscint scans, a monoclonal antibody to cardiac myosin is tagged with iodine 131, which may provide more direct evidence of myocardial damage and overcome some of the lack of specificity of MUGA scans. These scans have been used as an adjunct to MUGA scans in a randomized trial of epirubicin and dexrazoxane. To date, neither the parameters of diastolic dysfunction nor any of the newer nuclear imaging techniques have been sufficiently sensitive to replace MUGA scans.[22]

Measurement of cardiac troponins is a highly sensitive method of detecting myocardial cell injury in acute coronary syndromes and has led investigators to study the applicability of such measurements to assessing anthracycline-induced myocardial cell damage. Elevated serum troponin T levels in children receiving doxorubicin for acute lymphoblastic leukemia (ALL) have been demonstrated to predict the echocardiographic findings of left ventricular dilatation and left ventricular wall thinning months later.[23] In at least one series,[24] troponin I levels rose in anthracycline-treated patients before deterioration in LVEF was visible by MUGA scanning. Troponin I levels were elevated and correlated with a fall in LVEF in breast cancer patients receiving high-dose chemotherapy with and without anthracyclines.[25] Markers of cardiac damage have not yet been demonstrated to help in making clinical decisions to continue or stop the administration of anthracyclines. The level of B natriuretic peptide, a measure of CHF, has also been used to monitor anthracycline-induced cardiac damage. [26] [27]

Anthracyclines cause a unique pattern of histologic damage, as was originally demonstrated in animal models and confirmed by endomyocardial biopsies in humans ( Table 63-3 ). A continuum of change is well described, from dilation of vacuoles to mitochondrial swelling, myofibrillar dropout, and, ultimately, cell death.[28] The changes that are seen on endomyocardial biopsy appear to parallel the clinical findings, and there is a good correlation with the clinical examination and results of MUGA scans.[29] The consistency of these findings among nonmammalian species has provided the basis for a number of animal models of anthracycline cardiomyopathy.[30]


Table 63-3   -- Histopathologic Scale of Doxorubicin Cardiomyopathy,[*]

Grade 0

Within normal limits

Grade 1

Minimal numbers of cells (<5% of total number of cells per blocks) with early change (early myofibrillar loss or distended sarcoplasmic reticulum)

Grade 1.5

Small group of cells involved (5% to 15% of total number), some of which have definite change (marked myofibrillar loss or cytoplasmic vacuolization)

Grade 2

Groups of cells (16% to 25% of total number), some of which have definite change (marked myofibrillar loss or cytoplasmic vacuolization)

Grade 2.5

Groups of cells involved (26% to 35%), some of which have definite change (marked myofibrillar loss or cytoplasmic vacuolization)

Grade 3

Diffuse cell damage (>35% of total number of cells) with marked change (total loss of contractile elements, loss of organelles, mitochondrial, and nuclear degeneration)

Adapted from Billingham ME, Mason JW, Bristow MR, Daniels JR: Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep 1978;62:865.

*

Other grading scales that may incorporate an intermediate grade of 0.5 are sometimes encountered. The individual defined grades are uniform between these various scales. (Mackay B, Ewer M, Carrasco CH, Benjamin RS: Assessment of anthracycline cardiomyopathy by endomyocardial biopsy. Ultrastruct Pathol 1994;18:203–211.)

 

 

The principal advantage of endomyocardial biopsy is the relative specificity of the test. The procedure is usually done by performing a right heart catheterization and using a specially designed bioptome to obtain a number of small tissue fragments from the interventricular septum. These are fixed for routine histologic examination using hematoxylin and eosin or are fixed in glutaraldehyde for examination under the electron microscopic. The procedure is usually performed on an outpatient basis, and in experienced hands, the incidence of serious complication is less than 1%.[31]

The disadvantages of endomyocardial biopsy include the necessity for special expertise in obtaining and interpreting the biopsies, the cost, and the possible, though low, risk of complications. In the modern clinical setting, it is unusual to need biopsies for arriving at appropriate medical decisions, but the biopsy still has a role in clinical investigation.

Decreasing Anthracycline Cardiotoxicity

Risk Reduction

The most obvious way to reduce risk is not to administer the medication at all or to discontinue it. Current approaches to risk reduction include changes in dose and schedule, use of analogs, new delivery systems, and specific blocking agents. Dose adjustment can be achieved by limiting anthracycline doses in patients at increased risk for toxicity or by empiric limitation of cumulative doses of doxorubicin to 400 to 450 mg/m2. Both of these approaches have merit, but neither prevents toxicity in all patients. Moreover, limiting therapy or discontinuing therapy prematurely could deprive patients who are not experiencing toxicity of therapy from which they are continuing to benefit. As has been noted, a combination of dose restriction with careful cardiac monitoring may offer the safest practical approach to patients receiving doxorubicin.[5] However, such strategies do have some risk of both suboptimal tumor management and cardiotoxicity.

Dose Schedule Changes

Alterations in the dose schedule of anthracyclines are based on the hypothesis that chronic cardiac toxicity is related primarily to peak drug concentration, whereas the antitumor effect is more related to total drug exposure (concentration time, or area under the curve). Clinical trials of weekly schedules versus those in which the drug is given every 21 days support this hypothesis: Weekly schedules resulted in decreased clinical toxicity[1] and improved endomyocardial biopsy scores.[32] Extending this approach to continuous infusion maximizes the reduction in plasma drug concentration while still maintaining oncologic effect. Several studies have demonstrated decreased cardiac toxicity with prolonged continuous infusions (e.g., 24 to 96 hours) compared with standard rapid infusion schedules.[33]The cardiac toxicity is less when measured by clinical examination, MUGA scan, or cardiac biopsy without apparent loss of antitumor efficacy. While all of the studies demonstrate that continuous infusion schedules clearly reduce cardiac toxicity, they do not totally prevent it. They do, however, allow significantly higher cumulative dosages to be administered with acceptable cardiotoxicity. In the case of doxorubicin, for example, approximately 900 mg/m2, or twice the usual cumulative dosage, can be given when the drug is administered by 96-hour continuous infusion. Mucositis is the factor that limits the duration of infusional regimens to a maximum of 96 hours. Continuous infusion schedules have not been universally accepted, in part because of the increased cost and the necessity for long-term or implantable access lines and infusion pumps.

New Delivery Systems

Liposomal drugs may permit more specific organ targeting of anthracyclines, thereby producing less systemic and cardiac toxicity. The drug can be incorporated into a variety of liposomal drug preparations. [34] [35] Initial activity was reported in Kaposi's sarcoma for daunorubicin[34] and doxorubicin.[35] More recently, activity also has been reported in ovarian cancer and breast cancer. In animal models, the pegylated liposomal preparation of doxorubicin, Doxil, is less cardiotoxic than is the free drug. In one trial, patients who were treated with the pegylated doxorubicin (Doxil) had lower cardiac biopsy scores (0.5 versus 2.25) than did controls who were treated with the standard doxorubicin protocol. [36] [37] Similar reductions in cardiac toxicity, as measured by biopsy score, were reported in a group of 29 women with breast cancer who were being treated with TLC D-99 liposomal doxorubicin, a new pegylated preparation.[38] Pegylated liposomal doxorubicin (PLD) consists of STEALTH technology-based liposomes containing doxorubicin HCL in an aqueous core. Liposomes are covered by surface-bound methoxypolyethylene glycol that is covalently linked to liposome phospholipids, utilizing the process called pegylation.[39] PLD takes advantage of its stable pegylated cover to be protected from enzymatic and phagocytic degradation. The small size of liposome (100 nm) enables drug preferential penetration through the compromised tumor vasculature and accumulation in tumors, thereby producing less systemic toxicity and less cardiac toxicity. In a phase III study of 509 women with metastatic breast cancer, 18.8% of patients in the doxorubicin arm developed decline in LVEF versus 3.9% of patients (all of them asymptomatic) in the PLD arm. Overall risk of cardiotoxicity was significantly higher in the doxorubicin arm than in the PLD arm (HR = 3.16, P < 0.001). Pegylated liposomal doxorubicin demonstrated efficacy comparable to that of doxorubicin (overall survival was 21 months for PLD versus 22 months for doxorubicin).[40] Other unique delivery systems that have not had significant clinical impact include starch microspheres,[41] albumic microspheres,[42] and lipiodol.[43]

Analogs

Analog development holds the promise of good antitumor activity with decreased cardiac toxicity. Many anthracyclines that are in clinical use (e.g., epirubicin and esorubicin) have been shown to produce less cardiac toxicity in preclinical animal models and were developed as potentially less cardiotoxic compounds than doxorubicin. Although this is still an important avenue of research, it has not yet resulted in a major reduction in clinical cardiac toxicity when the drugs are administered at equimyelotoxic doses.[44] Twenty-five of 261 patients who received more than 600 mg/m2 of epirubicin (with single doses of epirubicin 45 to 90 mg/m2 day 1 and day 8 q 28 days) developed CHF (10%), including seven who died of cardiac toxicity.[44] In a later analysis, the same group reported that 59% of patients who had received 850 to 1000 mg/m2 of epirubicin exhibited a 25% fall in ejection fraction 3 years after the completion of epirubicin, and 20% developed symptoms of CHF. Therapy with angiotensin-converting enzyme (ACE) inhibitors reversed the clinical symptoms in most, but not all, cases.[45] Biopsy studies have been limited but suggest some cardiac protection over the native compound.[46] Some degree of cardiac toxicity indicated by a change in LVEF or development of clinical CHF was observed in patients receiving adjuvant therapy[46] with high doses (epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2)[47] or in combination with paclitaxel,[48] although in all of these, the incidence of clinical CHF was low. In the Canadian trial that compared FEC (5-fluorouracil [5-FU], epirubicin, and cyclophosphamide) to CMF (cyclophosphomide, methotrexate, and 5-FU), there was no clinical cardiac toxicity in the 351 patients in the FEC arm; one of the 359 patients in the CMF arm did show cardiac toxicity, however.[44]

Blocking Agents

Differences in the biochemical mechanisms of antitumor activity and cardiac toxicity provide a potential avenue of selectively inhibiting or preventing the adverse effect. Targets for this approach include agents that prevent free radical generation or salvage free radicals. Several free radical scavengers, including α-tocopherol (vitamin E),[49] N- acetyl cysteine,[50] coenzyme Q-10,[51] and prenylamine,[52]have been tested as selective cardiac protectors with negative or inconclusive results. Dexrazoxane (Zinecard) is the one drug that has been approved for this use and is clearly cardioprotective. The compound is a bisdioxopiperazine that is hydrolyzed intracellularly to form a bidentate chelator, similar in structure to EDTA; it effectively binds intracellular iron. The putative mechanism of cardioprotection is that dexrazoxane strips Fe2+ from the iron-doxorubicin complex, thereby preventing free radical generation ( Fig. 63-4 ). Randomized trials in patients with breast cancer[18] and small cell lung cancer[53] indicate that dexrazoxane can reduce doxorubicin-induced cardiac damage as measured by clinical examination, MUGA scan or endomyocardial biopsy. Dexrazoxane's limiting toxicity of myelosuppression did not add significantly to the toxicity of the regimens. Conflicting results for its effect on antitumor activity have been reported, but most trials indicate no negative effects.[5]However, a possible increase in early disease progression in one large study has led to some concern.[54] Additional trials have suggested that the drug affords cardioprotection in breast cancer without interfering with antitumor efficacy. [55] [56] [57] Furthermore, analysis of randomized trials in breast cancer suggests that even when dexrazoxane is added after the sixth course of chemotherapy (300 mg/m2), there is significant cardioprotection while maintaining the antitumor activity of the regimen. This concern has led to limitation of its approval to metastatic disease after patients have received doxorubicin alone.[58] While these analyses argue for the use of this agent in the management of breast cancer, it is now clear that anthracyclines cause cardiac damage considerably earlier than had been previously appreciated, and protection after multiple cycles of chemotherapy might not represent the optimal approach to cardioprotection.[59] Coadministration of dexrazoxane with a less cardiotoxic doxorubicin analog could offer the best future means of reducing anthracycline-related cardiac toxicity. Of interest, dexrazoxane has been shown in animal systems to protect against the cardiotoxic effects of epidoxorubicin but may have less effect with mitoxantrone.[12] Clinical testing of dexrazoxane in combination with epidoxorubicin has been shown in randomized trials in women with breast cancer to protect against cardiac toxicity without inhibiting antitumor activity,[60] and these results have been extended to sarcoma treated with high-dose epirubicin.[22]

 
 

Figure 63-4  Proposed mechanism for ICRF-187 inhibition of doxorubicin Fe complex formation.  (From Muggia FM, Green MD, Speyer JL [eds]: Cancer Treatment and the Heart. Baltimore, Johns Hopkins University Press, 1992, p 27.)

 

 

 

Pediatrics

Overall, children are at increased risk for developing cardiac toxicity. In a large retrospective cohort study (Childhood Cancer Survivor Study), 10,397 survivors of childhood cancer were followed for a median of 17 years; the relative risk of grade 3 or 4 CHF was 15.1 (95% CI: 4.8 to 47.9); that of coronary artery disease was 10.4 (95% CI: 4.1 to 25.9 to 3.5).[61]

Children are particularly sensitive to treatment with anthracyclines. It occurs at relatively lower cumulative doses and appears to increase over time. In a study of 830 children treated in the Netherlands, the incidence of CHF with a median of 8.5 years follow-up was 2.5%, rising to 5.5% at 20 years. Higher cumulative doses were associated with greater risk, 9.8% in children who received greater than 300 mg/m2.[62] Longitudinal studies by Lipshultz and colleagues in 115 pediatric leukemia patients (median follow-up: 11.2 years) also indicated that cumulative anthracycline dose is the most important risk factor. However, many children developed significant changes in cardiac function at lower doses (228 mg/m2); 59% showed increased afterload, and 23% showed decreased contractility.[63] Younger age at treatment, radiation exposure, female sex, and tumor type are also risk factors.[64]

The pathophysiology of anthracycline cardiac damage in children appears to be a product of both direct myocyte damage and a progressive loss in heart muscle mass leading to decreased contractility. In the leukemia studies, the reduction in fractional shortening z-scores (related to impaired contractility and increased afterload) was progressive at more than 12 years follow-up.[63] Treatment is similar to that with adults. Enalapril and ACE inhibitor may delay the pathologic process but do not prevent it.[64] Dexrazoxane (Zinecard) however can prevent or significantly reduce anthracycline cardiac toxicity. It was first reported by Wexler in a group of children with pediatric solid tumors.[65] In a larger randomized trial involving 206 children with ALL receiving doxorubicin, cardiac injury measured by rise in troponin T levels was observed in 21% of children receiving dexrazoxane versus 50% in those receiving doxorubicin alone (P < 0.001). Moreover, there was no evidence that dexrazoxane compromised the treatment efficacy. At 2.5 years, the event-free survival and continuous complete remission rates were 83% and 81%, respectively, for both groups.[66]

Other Causes of Congestive Heart Failure

Chemotherapy

TRASTUZUMAB.

Trastuzumab (Herceptin) and possibly related compounds are the chemotherapeutic agents that are most associated with CHF other than the anthracyclines. Although the signs and symptoms of heart failure are the same, the clinical course and pathophysiologic mechanism may be quite different. Combinations of trastuzumab with other cardiotoxic agents, including the anthracyclines, may cause additive or synergistic toxicity. The monoclonal antibody to Her2/neu receptor, trastuzumab, is widely used in breast cancers that overexpress Her2/neu. The significant reduction in risk of recurrence when applied in the adjuvant setting means that many more patients will be receiving this drug. Cardiac toxicity was reported in the single-agent phase II trial reported by Cobleigh and coworkers.[67] In the pivotal stage III trial in metastatic disease that led to initial drug approval, an unexpectedly high incidence of cardiac toxicity was observed: 27% when an anthracycline and cyclophosphamide were combined with trastuzumab compared with 8% with the chemotherapy alone. A similar though smaller effect (13% versus 1%) was observed when paclitaxel was combined with trastuzumab. It should be noted that all of the patients who were treated with paclitaxel had received prior anthracyclines.[68] Seidman and colleagues reviewed the records of 1219 patients in seven trastu zumab trials.[69] They report an incidence of cardiac dysfunction of 3% to 7% with trastuzumab alone, 27% with anthracycline and cyclophosphamide, and 13% with paclitaxel. Further data from prospective trials are still necessary to better quantify the contribution of trastuzumab to chemotherapy-induced toxicity.[70] In the NSABP B31 adjuvant breast cancer trials, 3-year cumulative incidence of grade 3 and 4 toxicities were reported in 4.1% of patients receiving trastuzumab after doxorubicin and cyclophosphamide followed by paclitaxel chemotherapy compared to 0.8% of patients who received chemotherapy alone.[71] Additional questions that are being addressed in several large trials include the relative effects of the duration and sequence of trastuzumab therapy combined with chemotherapy. The addition of carboplatin to paclitaxel and trastuzumab does not appear to increase cardiac toxicity,[72] nor does the combination of vinorelbine and trastuzumab. [73] [74] Cardiac observations with combinations of trastuzumab and gemcitabine, capecitabine, and other drugs are underway. The lesser cardiotoxic potential of liposomal doxorubicin led to a recently completed a trial of 30 patients with metastatic breast cancer who were treated with PLD in combination with trastuzumab. In this relatively small study, 10% of patients developed asymptomatic decline in LVEF of at least 15%. No symptomatic CHF was observed.[75]Trastuzumab-induced cardiac toxicity differs from anthracycline cardiac toxicity in the following ways:

  

   

It is not dose related.

  

   

It is usually reversible. In one report, 79% of patients responded to medical management, yet some also recover without specific treatment.

  

   

Many patients can be successfully rechallenged after a return of cardiac function to normal without symptom recurrences or further deterioration on LVEF.

  

   

It does not present with the same ultrastructural changes on endomyocardial biopsy.

  

   

The biochemical mechanisms of damage are different.

In recognition of these important differences, Ewer and Lippman have proposed a classification system of chemotherapy-induced CHF that divides anthracycline-induced cardiac damage (type I) from trastuzumab damage (type II).[1] We propose further revising this system to include other causes of cardiac damage in cancer patients (see Fig. 63-1 ).

There is increasing knowledge about the mechanism of trastuzumab cardiac toxicity that points to a role of inhibition of normal cardiac repair pathways. This would explain the increased toxicity when trastuzumab is combined with doxorubicin and might suggest additive toxicity with other sources of cardiac stress. Her2 heterodimerizes to Her4, leading to autophosphorylation of the Her2 tyrosine kinase domain.[76] This complex, which is the antitumor target of trastuzumab, is also active in cardiac repair. The complex is activated by neuregulin 1, which is secreted in paracrine fashion by cardiac endothelial cells that are under stress.[76] Activation of the complex leads to multiple downstream effects that in turn lead to hypertrophy of cardiac myocytes in vivo. In mice, deletion of Her2 results in a dilated cardiomyopathy.[77] Chien proposed a model in which various types of cardiac stress such as mechanical strain, anthracyclines, or hypoxia trigger two competing pathways of cardiac myocyte survival (mediated by neuregulin-1 or gp 130 cytokines) or apoptosis. The clinical outcome depends on which process prevails. In this model, treatment with trastuzumab blocks the survival pathway by preventing Her2/Her4 heterodimerization, thus shifting the balance to apoptosis. The result is decreased cardiac contractility and CHF.[78]

LAPATINIB.

Oral lapatinib (Tykerb) is a small molecule dual selective inhibitor or ErbB1 (EGFR) and ErbB2 (Her2/neu) tyrosine kinases. In part because of the cardiac effects of trastuzumab, cardiac function has been carefully monitored in early clinical trials. Isolated cases of clinical CHF with reduction in LVEF were reported in early phase I and II trials. In a retrospective analysis from 3500 patients from all reported trials, Perez and colleagues reported a 1.3% incidence of asymptomatic CHF and a 0.1% incidence of symptomatic CHF. Because of the possibility of interactions with other agents, cardiac toxicity is still carefully monitored in current trials of this agent.[79]

MITOXANTRONE.

Mitoxantrone was developed primarily as a noncardiotoxic analog of the anthracyclines. It is an anthracendione that lacks the amino sugar that is common to anthracyclines. Data from collected single-agent studies and two randomized studies indicate that mitoxantrone may result in a congestive cardiomyopathy but at a lower incidence than doxorubicin when equimyelotoxic doses are compared.[80] The incidence of cardiotoxicity at cumulative doses of greater than 160 mg/m2 is about 5%, although the incidence of clinical CHF is less than 2%. The clinical presentation is similar to that seen with doxorubicin. The diagnostic evaluation and endomyocardial biopsy changes are similar to those seen with doxorubicin. The biochemical mechanism of damage is not clear. Prior therapy with doxorubicin increases the risk of mitoxantrone cardiac toxicity; changing from one anthracycline to another or to an analog might not protect from cardiotoxicity. As was stated previously, the mechanism of cardiac toxicity might not be the same as for doxorubicin.

Phosphoramide Mustards.

High-dose intravenous cyclophosphamide infusion (120 to 240 mg/kg over 1 to 4 days) has been associated with CHF and death from hemorrhagic myocarditis. [81] [82] In contrast to that from anthracyclines, cardiac toxicity from cyclophosphamide is acute and is not related to the cumulative dose. Mortality is high in the face of fulminant hemorrhagic myocarditis. The majority of patients who are treated with high-dose cyclophosphamide will demonstrate a decrease in QRS voltage and a decrease in systolic function, which often are asymptomatic and reversible. Postmortem studies and an experimental animal model suggest that the loss of systolic function is due to direct endothelial injury resulting in capillary microthrombosis and interstitial fibrin deposition.

IFOSFAMIDE.

Ifosphamide also has been associated with the development of CHF in a dose-dependent fashion. In one series of 52 patients receiving a high dose (10 to 18 g/m2) as part of high-dose chemotherapy with ABMT, 9 patients (17%) developed CHF (8 severe enough to require admission to the intensive care unit) at a mean of 12 days (range: 6 to 23 days) after therapy.[83] Most of these patients received prior doxorubicin, raising the possibility of sequential stress. Of interest, autopsy data (endomyocardial biopsies were not performed) did not reveal hemorrhagic myocarditis.

INTERLEUKIN-2.

The major cardiovascular effects of interleukin-2 (IL-2) include hypotension (secondary to decreased peripheral vascular resistance), dysrhythmias, and ischemia. Primary myocardial suppression is also suggested by a decrease in LVEF and an increased end-diastolic volume. This results from inadequate cardiac compensation in the face of changes in peripheral resistance.[84]

IMATINIB.

Imatinib (Gleevec), an oral agent small molecule that competes for BCR-ABL, C-KIT, PDGFR, and ABL-2 protein kinase-binding sites by impeding protein kinase phosphorylation and activation of downstream kinases, has significant activity in chronic myeloid leukemia (CML) and some activity in ALL and gastrointestinal stromal tumor and may also have cardiac side effects. Although no cardiac events were noted in a series of 553 CML patients receiving imatinib,[85] two cases of CHF with elevated BNP levels were reported in patients with gastrointestinal stromal tumor,[86] and 10 patients (8 CML, 1 ALL, 1 myelofibrosis) with CHF were reported by Kerkela and colleagues[87] In two patients, pathologic whorls suggestive of toxic myopathy (but different from anthracycline effects) were observed on endomyocardial biopsy. A murine model with imatinib revealed similar findings and a dilated cardiac myopathy. There is controversy about the extent of this problem. The mechanism of imatinib toxicity, if it exists, is probably through a type II mechanism (see Fig. 63-1 ). The actual incidence or significance of these findings is a matter of debate but has led to a cautionary warning by the manufacturer.[88]

SUNITINIB.

Sunitinib (Sutent) is an oral agent and a small molecule that inhibits PDGFR, VEGFR, KIT, FLT3, CSF-1R, and RET tyrosine kinases that are important for tumor cell growth, survival, metastases, and angiogenesis. In two studies of 169 patients with metastatic renal cell carcinoma who failed prior cytokine-based therapy, the drug showed that 14% of patients had declines in LVEF below normal level. In the first study, 4.7% of patients had a LVEF drop of 20% or more with no reported symptoms.[89] In addition, grade 3 hypertension was reported in 6%. In the second study, one patient developed dyspnea.[90] However, in another study of 207 patients with gastrointestinal stromal tumor, there were no cases of decrease in LVEF or CHF.[91] At this time, the drug maker recommends stopping sunitinib in the event of clinical heart failure and interrupting and/or reducing the dose in asymptomatic patients with an LVEF drop of less than 50% or in those with LFEV more than 20% below baseline.[92]

OTHER COMBINATIONS.

Combinations of chemotherapeutic agents have been reported to cause varying degrees of CHF. When doxorubicin was first combined with paclitaxel, an 18% incidence of CHF was reported with cumulative doxorubicin doses of 400 mg/m2.[93] Not all investigators reported this high rate, however.[94] When the paclitaxel was initially administered as a 24-hour infusion, increased plasma and tissue concentrations of doxorubicin and the doxorubicinol metabolite were observed. Limiting the doxorubicin dose and allowing for an interval between doxorubicin and paclitaxel administration reduced the incidence of CHF to 4.7% of 657 patients, with a higher incidence of 25% in patients who received more than 440 mg/m2.[95] Combinations of doxorubicin with docetaxel have not been associated with increased cardiac toxicity. In a randomized trial comparing doxorubicin and docetaxel with doxorubicin and cyclophosphamide in 429 women with breast cancer, CHF was not increased (3% versus 4%), and the decline in LVEF—30 points from baseline—was less (1% compared with 6%).[96] The incidence of CHF has been reported to be 6% for the combination of epidoxorubicin and paclitaxel.[97]Several trials have raised the possibility of increased cardiac toxicity when doxorubicin is combined with high-dose cyclophosphamide[98] in the transplant setting.

Radiation

Radiation to the myocardium can cause interstitial myocardial fibrosis. This occurs through capillary damage, organization of fibrinous exudates with microcirculatory damage, and fibrosis.[99]Echocardiography and MUGA scans can help to differentiate primary myocardial damage from the pericardial damage that often occurs in the same patients.[100] Repeated doses or very high radiation doses (>6000 cGy) are associated with a greater risk of radiation damage. Biventricular dysfunction is common, although usually asymptomatic, occurring 5 to 20 years after radiation therapy. This is especially likely in patients who have been treated through a single anteroposterior port.[101] As a result of advances in radiotherapy techniques, clinically significant radiation-induced myocarditis is rare; presumably, the rates of late dysfunction will become less frequent as well.

Serial large retrospective reviews suggest that radiation therapy to the heart leads to increased mortality. Breast cancer cohorts in which the radiation dose to the heart varies depending on whether the cancer was in the right or left breast provide evidence for assessing this toxicity. In a meta-analysis of 40 trials from the 1980s of more than 19,000 women with breast cancer who were treated with radiation, the Early Breast Cancer Trialists Collaborative Group (2000) found an increased mortality from cardiovascular disease.[102] However, a more recent study with up to 15 years of follow-up of more then 15,000 breast cancer patients who were treated with more modern heart-sparing techniques revealed no excess in cardiac disease among those who were treated for left-sided versus right-sided breast cancer.[103] In another retrospective study of 27,283 patients, there was a progressive 6% yearly decline in ischemic heart disease hazard of death in patients with left-sided breast cancer versus right-sided breast cancer who were treated with radiation after 1979.[104] In the largest data analysis of 308,861 women from U.S. Surveillance Epidemiology and End Results, 115,165 of whom had been treated by radiation, Darby and colleagues found progressive decrease in the cardiac mortality ratio (left versus right tumor) from 1.42 after 10 to 14 years for those irradiated in 1972 to 192 to 1.27 after 10 years for those irradiated in 1983 to 1992.[105] Harris and colleagues studied long-term side effects (median follow up of 12 years) of radiation therapy of 961 breast cancer patients treated with right-side versus left-side heart irradiation with lower volume of heart exposure techniques used in University of Pennsylvania since 1977. Although “there was no difference in overall mortality from any cardiac cause,” the authors found a 6.4% cumulative risk of cardiac death for the left-sided irradiation versus 3.6% for right-sided irradiation at 20 years.[106] The new methods of radiation therapy, such as tomotherapy, intensity-modulated radiation therapy, mixed electron/photon beams, respiratory gating,[107] and prone accelerated partial breast irradiation,[108] have a potential of further decrease of radiation-caused cardiac mortality and morbidity.

Increased caution must be exercised, however, when radiation therapy is combined with doxorubicin therapy or possibly other cardiotoxic drugs because there appears to be a synergistic toxic effect on the myocardium. This can occur even if the two therapies are separated by long time periods. Prior radiation is a well-recognized risk factor for developing doxorubicin toxicity.[109] Conversely, radiation can cause a sudden decrease in ventricular function in a patient who either is receiving or has received doxorubicin. There are insufficient data to assess a possible interaction between radiation and trastuzumab therapy.

Therapy

Treatment of all cardiomyopathies is similar, regardless of their etiology ( Box 63-1 ). Ceasing treatment with the offending agent is of prime importance, and changing from one agent to another, especially when an anthracycline is involved, will not protect from further cardiotoxicity. Fluid and sodium restriction and the use of diuretics may provide some relief in acute situations. Afterload reduction with agents such as ACE inhibitors is clearly beneficial, and in stable patients, beta-adrenergic blockers such as carvedilol appear to be of significant benefit.[110] Clinical improvement in anthracycline-induced CHF has been demonstrated, as has improvement in LVEF as measured by serial MUGA scans. [17] [111] In an animal model, treatment with angiotensin II receptor blockers may also be of benefit.[112]Currently, no therapy is available that can reverse the damage done to the injured myocardium; and dexrazoxane, despite its mechanism of protection in the acute stage of cardiac damage, would not be expected to repair existing damage. Early treatment of significant cardiac dysfunction may mitigate the progression of disease. Digitalis can improve symptoms but probably does not extend life.

Box 63-1 

DOXORUBICIN-INDUCED CARDIOMYOPATHY

Monitoring

  

   

Physical examination is the best way to monitor patients for doxorubicin-induced cardiomyopathy (e.g., sinus tachycardia is a nonspecific early sign), with radionuclide scans or echocardiograms at baseline, 300 mg/m2, 450 mg/m2, and each 100 mg/m2 thereafter.

  

   

Patients who are at increased risk—for instance, those who have had prior treatment with anthracyclines, are older than 70 years of age, have had prior chest radiation therapy, or have pre-existing cardiac disease—might need to be observed more closely. Therapy should be withheld if the left ventricular ejection fraction falls to less than 0.45 or to 0.2 below baseline. (Other investigators have used a fall of 0.15 as the cutoff for discontinuing therapy.)

  

   

Most centers still use endomyocardial biopsy as the confirmatory tool. Biopsy should be considered in patients with a cumulative dose of 450 mg/m2 or more, and therapy should be withheld in any case if the Billingham biopsy score is 2 or greater.

  

   

Cardiac troponin C and I are under investigation for monitoring purposes.

Cumulative Dose Limitation

If monitoring strategies are in place, most patients who are thought to be benefiting from therapy can be safely treated to doses exceeding 450 mg/m2.

Dosage Schedule Modification

The incidence of cardiomyopathy may be decreased by modifying the dose schedule. For example, intravenous bolus schedules may be adjusted by dividing the 21-day dose into three weekly doses or a continuous infusion schedule in which the full dose is given over 72 to 96 hours through central catheters with portable infusion pumps.

Cardioprotection

Dexrazoxane (ICRF-187: ADR 529), a chelating agent that binds intracellular iron and prevents free radical production, has been shown in clinical trials to markedly reduce the incidence and severity of cardiomyopathy.

Treatment

  

   

The first step in treatment is to stop the doxorubicin and then not to use it again in the future. As with other cardiomyopathies, fl uid intake is limited.

  

   

Sodium, diuretics, afterload, and cautious use of afterload reduction, especially with angiotensin-converting enzyme inhibitors, may result in clinical improvement.

  

   

The course can vary, ranging from improvement to steady worsening with biventricular failure and death as the outcome.

CONGESTIVE STATES ASSOCIATED WITH OTHER CANCER TREATMENT

General considerations of fluid and electrolyte management should be carefully considered in administering anticancer treatment. Possible fluid overload states can result from intensive hydration regimens (e.g., for cisplatin) or with transfusion. Patients with anemia and low serum albumin are more susceptible to high output states. Malignant pleural and pericardial effusions, as well as ascites or intrathoracic malignancies, can cause external compression of the heart with resulting symptoms of CHF. Thyroid dysfunction sometimes is identified in cancer patients and responds to the usual therapeutic interventions.

DYSRHYTHMIAS

Dysrhythmias are commonly seen in the course of treatment of malignancies. The entire spectrum of supraventricular and ventricular bradydysrhythmias and tachydysrhythmias can be seen in cancer patients for a variety of reasons that might or might not be related to the cancer or its treatment. These include intracardiac or paracardiac tumor, electrolyte imbalance, fever, and hyperadrenergic states. Dysrhythmias related to therapy may, in turn, be related to coronary or myocardial disease resulting from anticancer therapy or to the direct dysrhythmogenic effects of the anticancer therapy itself.

Radiation injury has been implicated in the development of sinus node dysfunction, atrioventricular block, and conduction disturbances below the bundle of His.[113]

Occasional dysrhythmias have been reported with the anthracyclines. While these usually occur in the setting of the drug-induced cardiomyopathy, the dysrhythmias are not a prominent part of the clinical picture. Sinus tachycardia, however, is exceedingly common in patients with an anthracycline-induced cardiomyopathy and may be the earliest sign of the cardiomyopathic effect of anthracyclines. Supraventricular dysrhythmias also may occur with the development of pulmonary venous hypertension. Ventricular dysrhythmias occur in the setting of left ventricular failure. Sudden death, however, remains rare.

Arsenic trioxide (Trisenox), an important agent for treatment of acute promyelocytic leukemia, has been reported to cause cardiac arrhythmias associated with QT interval prolongation[114] as well as complete atrioventricular block. [114] [115] QT prolongation can be a risk factor for torsade de pointes, a life-threatening form of ventricular arrhythmia.[116] The prevalence of QT prolongation increased from 14.4% at baseline to 68% of treated patients in one study.[114] However, in the same study, analysis of 99 patients and 1189 electrocardiographic recordings suggests that QT prolongation may be a reversible effect, provided that careful patient cardiac evaluation is done before and during therapy as well as detection and timely correction of electrolyte abnormalities. Indeed, only 2 patients out of 99 developed significant arrhythmias.[114] Rare deaths have been reported; female gender and African extraction may be risk factors, but further study is needed. Reports are anecdotal.

Taxol has been implicated in the development of dysrhythmias. A 30% incidence of asymptomatic bradycardia has been observed with this agent; however, the bradycardia seldom requires termination of the agent. In addition, atrioventricular block of varying degrees, bundle branch block, and ventricular tachycardia have been described[117] and may require specific therapy. Supraventricular tachycardias were reported in 8 of 41 (20%) patients receiving therapy with dihydro-5-azacytidine, an investigational pyrimidine, for mesothelioma.[118]

Interleukin-11 (Neumega) is used for the reduction of chemotherapy-induced thrombocytopenia. In one trial, 6 of 58 patients (10%) developed symptomatic dysrhythmias.[119] Five patients had atrial fibrillation, and one patient had atrial flutter. The authors speculated that these effects might have been secondary to fluid retention.

Dysrhythmias also have been reported with the monoclonal antibody to CD20 (Rituximab).[120]

Nonspecific dysrhythmia is common in cancer patients and might be due to fluid and electrolyte shifts associated with vomiting, as well as hyperadrenergic states that may accompany anemia and a variety of other factors. Most of these rhythm disturbances can be managed with correction of the underlying abnormality and do not require specific antidysrhythmic therapy.

MYOCARDIAL ISCHEMIA

A variety of ischemic syndromes have been ascribed to oncologic therapy. Much of the data is anecdotal, however, as there is a high incidence of coronary artery disease in the population in which cancer is also common. Chemotherapy may shift a previously stable oxygen supply and demand balance in favor of an increased demand in the face of a fixed supply that results in the ischemic syndrome. The clinical picture is further confused by the high incidence of intercurrent intrathoracic malignant disease, anemia, fever, and infections and concomitant treatment with other drugs, all of which can affect the balance. Furthermore, the malignancy itself may cause chest pain in a patient with noncritical ischemic disease.

There is, however, convincing evidence that thoracic radiation therapy is associated with the development of coronary artery disease.[121] In addition to the very substantial body of evidence that radiation causes small vessel damage, which ultimately leads to myocardial fibrosis and cardiomyopathy, there also are data that implicate radiation therapy in the development of epicardial (particularly ostial) coronary artery disease. [121] [122] The original data came largely from case reports of myocardial ischemia and infarction in young adults (without other risk factors for coronary atherosclerosis) following mediastinal radiation therapy. Two basic pathologic mechanisms have been implicated. The first relates to the direct effects of radiation on the endothelial cells of epicardial coronary arteries, leading to accelerated atherogenesis. The second—and more typical—pathology is that of severe medial and adventitial fibrosis, perhaps mediated through radiation damage to the vasa vasorum. Typically, this vessel fibrosis is associated with a paucity of the intimal lipid deposition that characterizes atherosclerotic lesions. [123] [124] [125] With newer cardiac-sparing radiation therapy techniques, the likelihood of cardiac damage has been reduced.

Fluoropyrimidines are the most commonly chemotherapy drugs associated with myocardial ischemia. The largest number of cases of ischemia that have been ascribed to anticancer therapy are associated with treatment with 5-FU.[126] Several case reports called attention to this possible association. There have been isolated reports of patients with normal coronary angiography who developed typical symptoms and electrocardiographic evidence of ischemia after 5-FU infusion, but a review of over 1000 patients receiving 5-FU revealed an incidence of cardiac toxicity of 4.5% in patients in whom coronary disease was known to predate treatment compared to an incidence of 1.1% in those not known to have coronary artery disease prior to therapy. Thus, it was not surprising that an early prospective analysis was not convincing for a causative role of this drug in the development of angina or myocardial infarction. In a prospective series of 910 patients,[127] however, 5 patients (0.55%) developed signs and symptoms that were consistent with coronary artery spasm. All five patients had ST segment elevation and ventricular dysrhythmias. Four had documented infarction, and two had cardiac arrests, leading to the hypothesis that there might be 5-FU- or metabolite-mediated increases in coronary vasomotor tone. Coronary artery spasm as a mechanism for 5-FU-associated ischemia could explain the increased incidence of ischemia in patients with underlying coronary disease as well as in those with angiographically normal coronary vessels. Nitrates and calcium blockers may be protective. There is some suggestion that the association of 5-FU with myocardial ischemic events is more striking in patients who are treated with continuous infusion therapy.[126] The association is more common in patients who are receiving concomitant radiation therapy[128] or treatment with cisplatin.

Capecitabine (Xeloda), an oral prodrug for 5-FU, has also been associated with cardiac toxicity. In a review of 832 patients, incidence was similar to that with 5-FU (3% for all toxicities and 1% for grades 3 to 4). Individual cases of myocardial infarction, angina pectoris, myocardial ischemia, myocarditis, and tachycardia were described.[129] It is possible that combination with oxaliplatinum may increase this toxicity. In combined data from two trials of 153 patients, cardiac toxicity was observed in 6.5% of patients; 4.6% were ischemic.[130]

Although the vinca alkaloids also have been reported to precipitate angina and myocardial infarction,[131] this observation is strictly anecdotal.

PERIPHERAL VASCULAR DISEASE

Raynaud phenomenon has been described in patients receiving cisplatin-based therapy.[132] It also has been described after therapy with vinblastine, vincristine, and bleomycin. These may be similar in mechanism to other ischemic syndromes (e.g., coronary ischemia or cerebral vascular ischemia), which have been described with these agents as well as 5-FU. Increased thromboembolism has been observed when thalidomide is combined with doxorubicin[133] and with gemcitabine and infusional 5-FU.[134] A similarly high incidence of thromboembolic events was reported with the combination of gemcitabine, cisplatin, and SU5416.[135] As is the case for radiation-induced coronary artery disease, clinically significant occlusive lesions in other arteries, such as the carotids,[136] have been reported following irradiation.

PERICARDIAL DISEASE

Most pericardial disease presenting in cancer patients may be attributed to the underlying malignancy, the most common malignancies being melanoma, breast cancer, and lung cancer. Patients may have metastatic disease to the pericardium or obstruction of lymphatic or venous flow, producing a pericardial effusion. Even in patients without clinically manifest disease, asymptomatic pericardial effusions are common. Pericardial effusions have been ascribed to the anthracyclines[137] as well as cyclophosphamide[138] and dihydro-5 azacytidine.[118] With the exception of irradiation, pericardial manifestations of cancer treatment are seldom troublesome. Interestingly, in series in which pericardial effusions were reported with doxorubicin or cyclophosphamide, most patients ultimately went on to demonstrate evidence of myocardial toxicity from the drugs. Isolated pericarditis was rare.

There have been case reports of high-dose busulfan causing cardiac tamponade in children with thalassemia[139] and a report of busulfan-related endocardial fibrosis.[140]

FLUID RETENTION

Docetaxel (Taxotere), an active taxane analog of paclitaxel (Taxol), has broad antitumor activity but is associated with fluid retention in some patients. Severe fluid retention and CHF are rare. This syndrome is progressive with more treatment cycles. It does not appear to be of cardiac or renal origin. Premedication with steroids substantially reduces this problem.[141]

Dasatinib (Sprycel) is an oral agent that is active in 14 of 15 imatinib-resistant BCR-ABL tyrosine kinase mutants and inhibits other tyrosine kinases such as SRC, C-Kit, and PDGFR. In a study of 84 CML and Ph+ ALL patients, 15% of patients developed pleural effusion, 19% developed peripheral edema, 14% developed pulmonary edema, and 7% developed pericardial effusion.[142] Also in studies of patients with leukemia, dasatinib caused QT prolongation in nine patients, three of whom (<1%) had QTcF greater than 500 msec.[143] Therefore, special attention should be paid to correction of hypokalemia and hypomagnesemia prior to dasatinib treatment as well as to patients with known QT prolongation and patients who are taking other medicines that can cause QT prolongation.[143]

All-trans retinoic acid, an oral agent that overcomes promyelocyte retinoic acid receptor maturation block caused by a t(15,17)-related protein, has become an important part of acute promyelocytic leukemia treatment. The drug causes retinoic acid syndrome,[144] which consists of respiratory distress, hypoxemia, weight gain, pleural and pericardial effusions, pulmonary infiltrates, fever, hypotension, and acute renal failure, after a median of 11 days (2 to 47 days) in approximately 25% of treated patients.[145] The treatment is high-dose dexamethasone given as soon as the syndrome is suspected[144] and temporary discontinuation of all-trans retinoic acid, depending on the clinical situation.

RADIATION-INDUCED PERICARDIAL DISEASE

Pericardial disease is a well-known side effect of thoracic radiation therapy. Effusions have been reported in 6% to 30% of patients receiving radiation therapy to the chest using older radiation techniques.[146] Since the 1960s, there have been numerous reports of patients who had received high-dose mediastinal radiation for the treatment of lymphoma and ultimately developed pericardial disease. Similar reports ascribing pericardial disease to radiation therapy for breast cancer also appeared in the late 1960s.

The clinical spectrum of radiation-induced pericardial disease is wide. Acute pericarditis occurs in 10% to 15% of patients with Hodgkin's disease who receive more than 4000 rads to the mediastinum.[147]The clinical onset of symptoms related to the pericarditis is anywhere from 0 to 85 months after therapy, with a peak occurring between 5 and 9 months. The acute pericarditis may be symptomatic, with the patient experiencing chest pain and fever and the phy-sician noting a pericardial friction rub. However, acute pericardial inflammation probably is often asymptomatic. In any event, the acute pericarditis usually resolves spontaneously. In symptomatic patients, treatment with nonsteroidal anti-inflammatory drugs (including aspirin) or corticosteroids is probably warranted.[148]

The acute effects of radiation on the pericardium appear to be due to an increase in capillary permeability in the pericardium resulting in a fibrinous exudate. Ultimately, fibrosis and calcification can occur. Fewer than half of symptomatic and asymptomatic patients with acute pericarditis will go on to develop chronic pericardial disease or tamponade. Constrictive pericarditis has been described anywhere from 2 to 20 years after radiation. Signs of constriction may include a pericardial knock, Kussmaul's sign, peripheral edema, and evidence of bowel edema or hepatic congestion. The pericardium might appear thickened on a thoracic CAT scan or an echocardiogram. The diagnosis of constrictive physiology can almost always be confirmed by Doppler echocardiography. In such patients, pericardiectomy might be warranted; however, the surgery is often difficult and carries significant morbidity and mortality.

Radiation-induced pericardial disease depends on the extent to which the heart has received radiation and the dose of radiation delivered to the heart. With current techniques in mediastinal radiation, including the use of modern megavoltage equipment and the delivery of divided radiation to the anterior and posterior thorax with a subcarinal shell and intensity-modulated radiation therapy, it is likely that the incidence of pericardial disease has been significantly decreased, perhaps to the range of 2% to 2.5%.[149]

CARDIOCIRCULATORY EFFECTS OF BIOLOGIC RESPONSE MODIFIERS

Bevacizumab (Avastin) is a recombinant monoclonal humanized IgG1antibody that selectively interacts with vascular endothelial growth factor (VEGF) and competitively inhibits its binding to VEGFR-1 (Flt-1) and VEGFR-1 (KDR/Flk-1) endothelial cell surface receptors, thereby disrupting microvascular proliferation and metastasis of tumors. Bevacizumab showed its activity as an adjunct to cytotoxic drug combination and is approved for use in colon, lung, and breast cancer. An 8% to 18% incidence of grade 3 or 4 hypertension was found in many phase I and II studies.[150] In the phase III trial, there was an 11% incidence of grade 3 hypertension in the group of 393 patients who were treated with bevacizumab in combination with irinoitecan and 5-FU/leucovorin (B/IFL), as compared to the 2.3% in the group of 397 patients who were treated with IFL alone. Hypertension was successfully controlled with ACE inhibitors, diuretics, and other antihypertensive medications.[151] Rarely, the drug must be discontinued; the blood pressure might remain elevated despite treatment interruption.

Recombinant technology has made a number of new agents available for clinical trial. They have a variety of side effects. In some cases, these adverse effects may actively be the molecular indicator of a variety of cellular interactions. Hypotension and tachycardia are observed with a number of agents. With interferon-alpha, these have been reported in 6% to 14% of patients.[152] It is difficult in these studies to separate changes in blood pressure from dysrhythmias or ischemic events. Hypotension is a more consistent feature of interferon,[153] although fewer patients have received other biologic therapies.

Hypotension (along with dysrhythmias, ischemia, and decreased contractility) is a major side effect of interleukin-2 and was observed to occur in more than 70% of patients in the early IL2/LAK trials.[154]The primary mechanism appears to be decreased vascular resistance. [84] [155] In the early days of therapy, patients develop increased heart rate, increased cardiac index, and decreased left ventricular stroke volume work index, peripheral vascular resistance, and mean arterial blood pressure. The clinical presentation is similar to that of septic shock, with a vascular leak syndrome, fluid retention, and noncardiogenic pulmonary edema. The mechanism may be similar to that of septic shock, with induction of cytokines and effector cells and the release of vasoactive agents. Reductions in dose and continuous infusion schedules have lessened these toxicities [156] [157] [158] but also may decrease the antitumor effects.[159] In one study,[160] oral L-carnitine appeared to decrease these complications. IL-2 toxicity often requires intensive-care management, support with pressors, and, at times, ventilatory support.

Hypotension also has been described with tumor necrosis factor,[161] granulocyte macrophage colony-stimulating factor,[162] interleukin-11,[119] and monoclonal antibodies.[117] With tumor necrosis factor, the hypotension often is dose-limiting.[161] With granulocyte macrophage colony-stimulating factor, it is observed at high doses and is associated with a capillary leak syndrome and decreased peripheral resistance.[162] The mechanism with these two agents is not as well defined, nor is the clinical problem as acute as it is with IL-2. Hypotension also has been reported with interleukin-1 in phase I trials.[163]

The possibility of cardiac toxicity was raised in early trials of interleukin-4, especially when one patient was found to have biopsy-proven myocarditis.[164] Interleukin-6 has been associated with cardiac dysrhythmias.[165] Syncope or near-syncope was reported in 6 of 58 patients in a trial of IL-11 (5 patients at the 50-mg/kg level and 1 patient in the in placebo group). Six patients also had documented dysrhythmias.[119]

Changes in peripheral vascular resistance and hypotension may be generalized effects of biologic therapies. Further elucidation of their mechanisms and management is required.

The complexities of bone marrow transplantation have led to cardiac toxicity in a number of patients. In a series of 170 patients who were monitored prospectively, life-threatening pericardial effusions or cardiac arrest were observed in fewer than 2% of cases.[166] Decreased ejection fraction was observed in 17 patients. In a retrospective study of 138 patients treated with high-dose therapy and stem cell rescue, cardiotoxicity occurred in 17 patients. It occurred more frequently in patients with lymphoma and breast cancer.[167] It is difficult, however, to determine which of the many drugs used in the regimen, particularly the chemotherapy induction, is responsible for these changes.

LONG-TERM EFFECTS OF CHEMOTHERAPY

One additional caution must be raised. As an increasing number of patients are long-term survivors of childhood cancers, adult patients who received adjuvant therapy without disease recurrence, or long-term survivors of more advanced adult malignancies, unanticipated cardiovascular effects may be observed. Long-term observation and study of these patients are necessary. Identification of such effects may bring into question the overall risk-benefit ratio of the original treatment. In a long-term (median: 10.2 years) follow-up study of 992 males in the United Kingdom who had been treated with chemotherapy or radiation for testicular cancer, the incidence of cardiac events (angina, chest pain, or myocardial infarction) was increased when compared to controls treated with orchiectomy alone (chemotherapy alone: rate ratio = 2.59; radiation therapy: RR 2.40; and chemotherapy plus radiation: rate ratio = 2.78). Neither the radiation fields nor the specific chemotherapeutic agent (bleomycin, vinblastine, cisplatin, or carboplatin) fully explained these findings.[168]

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