Deborah L. Keefe

Cardiac Dysfunction in the Trastuzumab Clinical Trials Experience

PURPOSE This study sought to estimate cardiac dysfunction (CD) risk for patients receiving trastuzumab; to characterize observed CD by severity, treatment, and clinical outcome; to assess effects of baseline clinical risk factors on CD; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD. PATIENTS AND METHODS A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed. Predefined criteria were used for the diagnosis, and the New York Heart Association functional classification system was used to document CD severity. Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset. RESULTS Patients treated with trastuzumab were found to be at an increased risk for CD. The incidence was greatest in patients receiving concomitant trastuzumab and anthracycline plus cyclophosphamide (27%). The risk was substantially lower in patients receiving paclitaxel and trastuzumab (13%) or trastuzumab alone (3% to 7%); however, most of these patients had received prior anthracycline therapy. CD was noted in 8% of patients receiving anthracycline plus cyclophosphamide and 1% receiving paclitaxel alone. Most trastuzumab-treated patients developing CD were symptomatic (75%), and most improved with standard treatment for congestive heart failure (79%). CONCLUSION Trastuzumab is associated with an increased risk of CD, which is greatest in patients receiving concurrent anthracyclines. In most patients with metastatic breast cancer, the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab.

QTc interval prolongation associated with intravenous methadone

&NA; Numerous medications prolong the rate‐corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether‐a‐go‐go‐related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (±standard error) per patient in QTc intervals on and off methadone was 41.7 (±7.8) ms, p<0.0001. Mean difference in QTc intervals on and off morphine was 9.0 (±6.1) ms, p=0.15. The approximately linear relationship between QTc measurements and log‐dose of methadone was significant (p<0.0001). Methadone and chlorobutanol independently block IHERG in a concentration‐dependent manner with IC50 values of 20±2 &mgr;M and 4.4±0.3 mM, respectively. Chlorobutanol potentiates methadones ability to block IHERG. Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation.

Anthracycline-induced cardiomyopathy.

The highly active chemotherapeutic agents doxorubicin, duanorubicin, idarubicin, epirubicin, and mitoxantrone are also associated with acute, largely reversible cardiotoxic effects and a dose-related cardiomyopathy. This cardiomyopathy is characterized by minimal left ventricular enlargement and global systolic dysfunction, usually with associated mild to moderate mitral insufficiency. Historically, this was characterized by myocardial biopsy and radionuclide angiography. More recently, echocardiography has become the most widely available and cost-efficient tool for diagnosis. The precise mechanism of this toxicity has not been fully defined. However, the maximum tolerated cumulative dose can by increased by reducing peak drug levels and concurrent administration of the iron chelator, dexrazoxane. Because anthracycline-induced cardiomyopathy is largely irreversible and cumulative, prevention is the preferred strategy. Monitoring by assessment of left ventricular function by the most reproducible method available as patients approach potentially toxic doses can substantially reduce toxicity. Stress studies before major procedures such as bone marrow or stem cell transplants may be of benefit. This syndrome responds well to conventional therapy for congestive heart failure with angiotensin-converting enzyme inhibitors, digoxin, and diuretics. The beta-blocker carvedilol is often associated with significant improvement in ejection fraction and symptoms and spironolactone is well tolerated and often of benefit. The long-term outlook of the syndrome is much better than previously reported because of advances in therapy and prevention.

Clinical cardiotoxicity of 5-fluorouracil.

5‐Fluorouracil is widely known to be toxic to the hematopoietic and gastrointestinal systems. It also has cardiac toxicity, but this is perceived to be rare. During a 16‐month period from January 1990 through April 1991, approximately 910 patients were treated with 5‐fluorouracil. Five of these developed life‐threatening toxicity consistent with coronary artery spasm for an incidence of .55%. The acute events occurred on the third or fourth day of the 5‐day infusion and after the fourth intravenous bolus in the patient on bolus therapy. Each of the patients had ST elevation and ventricular arrhythmias, four had acute myocardial infarction, and two had cardiac arrests. In these cases and those previously reported, cardiac toxicity is consistent with drug‐ or metabolite‐mediated increases in coronary vasomotor tone and spasm, leading to the full spectrum of signs and symptoms of myocardial ischemia in susceptible individuals.

Intraoperative administration of the intravenous angiotensin-converting enzyme inhibitor, enalaprilat, in a patient with congestive heart failure

Patients with heart failure due to coronary artery disease can be managed by afterload reduction as long as myocardial oxygen consumption is not increased by tachycardia and coronary artery perfusion pressure is not compromised. Recently, angiotensinconverting enzyme (ACE) inhibitors have been introduced for this purpose, and the active form of the ACE inhibitor enalapril, enalaprilat, is now available in intravenous (IV) form. This report describes the intraoperative management of a patient with a history of heart failure and coronary occlusive disease who benefited dramatically from enalaprilat, as documented by both thermister-tipped pulmonary artery catheter monitoring and two-dimensional transesophageal echocardiography enhanced with color flow Doppler.

Lack of Increased Cardiac Toxicity with Sequential Doxorubicin and Paclitaxel

Introduction Recently, paclitaxel has joined doxorubicin as one of the most active single agents for the treatment of metastatic breast cancer (1,2). Because these drugs now appear to be non-cross-resistant, combinations have been studied using various doses and schedules to assess efficacy and toxicity (3-7). However, concurrent administration of the two drugs at full doses has been associated with increased toxicity. In particular, an increased incidence of congestive heart failure has been seen in two studies of doxorubicin plus concurrent paclitaxel (6,7). At our institution, we have been developing “dose-dense” chemotherapy applying doxorubicin, paclitaxel, and cyclophosphamide as adjuvant treatment for high-risk primary breast cancer. To minimize toxicity and maximize delivered dose intensity, these drugs are given sequentially in the above order rather than concurrently. Because of the suggestion that the use of doxorubicin and paclitaxel might increase the risk of cardiac toxicity, we reviewed our...

Intracardiac teratoma 15 years after treatment of a nonseminomatous germ cell tumor

A patient presented to our center with a 15-year history of medical, surgical and radiation treatment for a nonseminomatous germ cell tumor and contralateral seminoma. He experienced a cerebral infarction, which led to the diagnosis of an intracardiac tumor. The tumor was resected and found to be a mature teratoma. We discuss the diagnosis and management of this unusual metastatic nonseminomatous germ cell cancer.

Using the Electrocardiogram to Teach Clinical Pharmacology

T he electrocardiogram is frequently used to measure drug effects in pharmacologic and pharmacodynamic studies. Many drugs used in cardiovascular therapeutics affect the surface electrocardiogram in ways that are readily measurable and directly correlated with plasma drug level and dose. In addition, many other therapeutic agents have pharmacologic or adverse effects that can be detected on the electrocardiogram and this information may be used to diagnose or avoid toxicity. Examples of predictable pharmacologic effects of therapeutic agents include prolongation of the PR interval with beta blockers,’ verapamil2 and diltiazem,3 widening of the QRS and associated QTc prolongation with Vaughan-Williams type IA antiarrhythmic drugs such as quinidine4 and widening of the QRS alone with IC antiarrhythmic drugs such as flecainide.5 Type III antiarrhythmic drugs such as amiodarone6 and sotalol7 also dramatically increase the QT and slow heart rate but have little effect on the QRS width. Numerous poisons such as the organophosphate insecticides8 (parathion, phosdrin, phosphamidon) and arsenic9 may cause long QT intervals and “torsade de pointes,” and overdoses of therapeutic agents such as the tricyclic antidepressants’#{176}may do the same. In addition, the cardiac glycosides cause characteristic cardiac arrhythmias” for which specific therapy in the form of light-chain antibody fragments12 (which are highly effective for digoxin toxicity and somewhat less so for digitoxin toxicity) is available if these arrhythmias are recognized. The use of examples with case material adds to the interest of learning to interpret electrocardiograms and aids retention of the characteristic appearance of the electrocardiogram associated with specific drug effects. A glossary of terms used in this discussion is shown in the Table. Clinical electrocardiograms

Evaluation of Suspected Deep Venous Thrombosis in Oncologic Patients

Impedance plethysmography (IPG) and duplex scanning with color flow Doppler were performed in 100 consecutive high-risk patients with clinically suspected deep venous thrombosis. Risk factors included recent surgery (<three weeks) in 23%, malignant disease in 91%, clotting abnormalities in 32%, and limited activity in 70%. Lower limb findings of either edema, calf tenderness, or both occurred in 92%. There was agreement between the two tests in 76 patients (29 positive and 47 negative). In 12 patients the IPG was positive and the duplex negative. Four of these had extensive pelvic disease, 2 had lung cancer with an obstructive profile, and 2 had heart failure, all of which are known to cause false-positive IPG results. In the other 12 patients the IPG was negative and the duplex positive; however, 3 of these patients had nonocclusive thrombi, 5 had pelvic disease, and 1 had a hemiparesis of the involved lower limb. In 15 patients (11 with positive duplex studies and 4 with negative) a venogram was obtained and confirmed the results. All patients were followed up clinically and none developed complications suggesting inaccurate duplex results. In conclusion, the IPG is of limited utility in this population with a sensitivity of 71%, specificity of 80%, and false-negative rate of 29% when duplex Doppler and clinical outcome are used as the standard. Where available, duplex Doppler should be preferred for evaluation of suspected deep venous thrombosis in patients with extensive medical disease.

Tricuspid valve thromboembolus with recurrent pulmonary embolism--a case report.

The authors describe a fifty-one-year-old man with multiple pulmonary emboli in whom two-dimensional echocardiography clearly showed a large mobile thrombus transiently entrapped in the chordal apparatus of the tricuspid valve, a location rarely noted except in autopsy specimens. Subsequent lung scan and echocardiograms documented clinically silent nonfatal embolization of this large thrombus to the lungs. Whereas most patients with this form of thromboembolic disease come to either surgery or autopsy, this case demonstrates how the combination of echocardiography and lung scanning can be used to differentiate the etiology of some right-heart masses.