Volume 3, Number 12;  September 15, 2004

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 Resident Report 9/15/04 – Bruce Kalmin

Case:  A 62 year-old African-American woman with metastatic breast cancer presents to the emergency room with a 1-week history of increasing shortness of breath that interferes with her activities of daily living. She also complains of chest palpitations and new 2+ pillow orthopnea. She denies chest pain, fevers/chills, or cough/hemoptysis.

Patient was diagnosed in 1987 with a right-sided ductal carcinoma in situ for which she received a right lumpectomy and local radiation. She had no further complications until bilateral breast masses were discovered in 2002. An FNA of the right breast mass revealed ductal carcinoma, which was ER/PR positive, Her2/neu negative. Patient had 3 pleural effusions in 2003, which all were malignant in nature. Therefore, her cancer was considered metastatic. The patient received adriamycin/cyclophosphamide treatment for 4 cycles. Before initiating chemotherapy, a MUGA scan revealed an ejection fraction of 62%. No repeat MUGA or echocardiogram was performed after chemotherapy.

            On initial presentation, the patients vitals were: T 36.3, BP 160/109, HR 82, RR 20. Her cardiovascular exam revealed a laterally displaced PMI, regular rhythm, normal S1, normal S2, and an S3 gallop, a II/VI holosystolic murmur at the left lower sternal border that radiated to the axilla, and JVD 10-12 cm at 30 degrees. She had decreased breath sounds on the right with dullness to percussion and crackles 2/3 up the lung field. Her abdomen was soft, non-tender, and non-distended with normoactive bowel sounds. She had palpable hepatomegaly and no splenomegaly. Breast exam revealed previous right lumpectomy and scarring (presumably from radiation). She had no cervical, axillary, or inguinal lymph nodes.

CXR revealed a right chronic, loculated pleural effusion with adjacent consolidation and cardiomegaly with interstitial prominence. A CT scan revealed thickened right pleura with decreasing lung volume on the right when compared to one taken a year ago. There was a multiloculated complicated effusion on the right, increased in complexity since the previous CT scan. A transthoracic echocardiogram revealed an ejection fraction of 30%, mild concentric LVH, no obvious valvular abnormalities, and no pericardial effusion.

Clinical Question: 

What is doxorubicin (Adriamycin)-induced cardiomyopathy?

Readings:

  Link Directly to Fulltext Article at Publisher

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Unique Identifier:12767102

Authors: Swain SM. Whaley FS. Ewer MS.

Institution: National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20889, USA. swains@mail.nih.gov

Title: Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.

Source: Cancer. 97(11):2869-79, 2003 Jun 1.

Abstract: BACKGROUND: Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. A large-scale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin-related congestive heart failure (CHF) after a cumulative dose of 550 mg/m(2). To assess whether this estimate is reflective of the incidence in the broader clinical oncology setting, the authors evaluated data from three prospective studies to determine both the incidence of doxorubicin-related CHF and the accumulated dose of doxorubicin at which CHF occurs. METHODS: A group of 630 patients who were randomized to a doxorubicin-plus-placebo arm of three Phase III studies, two studies in patients with breast carcinoma and one study in patients with small cell lung carcinoma, were included in the analysis. RESULTS: Thirty-two of 630 patients had a diagnosis of CHF. Analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m(2). Age appeared to be an important risk factor for doxorubicin-related CHF after a cumulative dose of 400 mg/m(2), with older patients (age > 65 years) showing a greater incidence of CHF compared with younger patients (age < or = 65 years). In addition, > 50% of the patients who experienced doxorubicin-related CHF had a reduction < 30% in left ventricular ejection fraction (LVEF) while they were on study. CONCLUSIONS: Doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported. These findings further indicate that LVEF is not an accurate predictor of CHF in patients who receive doxorubicin.

 Link Directly to Fulltext Article at Publisher

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Unique Identifier:7760889

Authors: Lipshultz SE. Lipsitz SR. Mone SM. Goorin AM. Sallan SE. Sanders SP. Orav EJ. Gelber RD. Colan SD.

Institution: Department of Cardiology, Children's Hospital, Boston, MA 02115, USA.

Title: Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer.[see comment].

Source: New England Journal of Medicine. 332(26):1738-43, 1995 Jun 29.

Abstract: BACKGROUND. Late cardiotoxic effects of doxorubicin are increasingly a problem for patients who survive childhood cancer. Cardiotoxicity is often progressive, and some patients have disabling symptoms. Our objective was to identify risk factors for late cardiotoxicity. METHODS. We examined echocardiograms from 120 children and adults who had received cumulative doses of 244 to 550 mg of doxorubicin per square meter of body-surface area for the treatment of acute lymphoblastic leukemia or osteogenic sarcoma in childhood, a mean of 8.1 years earlier. Measurements of blood pressure and left ventricular function, contractility (measured as the stress-velocity index), end-diastolic posterior-wall thickness, end-diastolic dimension, mass, and afterload (measured as end-systolic wall stress) were compared with sex-specific values from a cohort of 296 normal subjects. RESULTS. All echocardiographic measurements were abnormal at follow-up a minimum of two years after the end of therapy, with more frequent and severe abnormalities in female patients. In a multivariate analysis, female sex and a higher cumulative dose of doxorubicin were associated with depressed contractility (P < or = 0.001), and there was an interaction between these two variables. Independent and significant associations were found between a higher rate of administration of doxorubicin and increased afterload (P < or = 0.001), left ventricular dilatation, and depressed left ventricular function; between a higher cumulative dose and depressed left ventricular function (P < or = 0.001); between a younger age at diagnosis and reduced left-ventricular-wall thickness and mass and increased afterload; and between a longer time since the completion of doxorubicin therapy and reduced left-ventricular-wall thickness and increased afterload (P < or = 0.001). CONCLUSIONS. Female sex and a higher rate of administration of doxorubicin were independent risk factors for cardiac abnormalities after treatment with doxorubicin for childhood cancer; the prevalence and severity of abnormalities increased with longer follow-up. CAS Registry/EC Number 23214-92-8 (Doxorubicin).

 Link Directly to Fulltext article in Ovid

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Unique Identifier:1997853

Authors: Lipshultz SE. Colan SD. Gelber RD. Perez-Atayde AR. Sallan SE. Sanders SP.

Institution: Department of Cardiology, Children's Hospital, Boston, MA 02115.

Title: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood.[see comment].

Source: New England Journal of Medicine. 324(12):808-15, 1991 Mar 21.

Abstract: BACKGROUND. Cardiotoxicity is a recognized complication of doxorubicin therapy, but the long-term effects of doxorubicin are not well documented. We therefore assessed the cardiac status of 115 children who had been treated for acute lymphoblastic leukemia with doxorubicin 1 to 15 years earlier in whom the disease was in continuous remission. METHODS. Eighteen patients received one dose of doxorubicin (45 mg per square meter of body-surface area), and 97 received multiple doses totaling 228 to 550 mg per square meter (median, 360). The median interval between the end of treatment and the cardiac evaluation was 6.4 years. Our evaluation consisted of a history, 24-hour ambulatory electrocardiographic recording, exercise testing, and echocardiography. RESULTS. Fifty-seven percent of the patients had abnormalities of left ventricular afterload (measured as end-systolic wall stress) or contractility (measured as the stress-velocity index). The cumulative dose of doxorubicin was the most significant predictor of abnormal cardiac function (P less than 0.002). Seventeen percent of patients who received one dose of doxorubicin had slightly elevated age-adjusted afterload, and none had decreased contractility. In contrast, 65 percent of patients who received at least 228 mg of doxorubicin per square meter had increased afterload (59 percent of patients), decreased contractility (23 percent), or both. Increased afterload was due to reduced ventricular wall thickness, not to hypertension or ventricular dilatation. In multivariate analyses restricted to patients who received at least 228 mg of doxorubicin per square meter, the only significant predictive factors were a higher cumulative dose (P = 0.01), which predicted decreased contractility, and an age of less than four years at treatment (P = 0.003), which predicted increased afterload. Afterload increased progressively in 24 of 34 patients evaluated serially (71 percent). Reported symptoms correlated poorly with indexes of exercise tolerance or ventricular function. Eleven patients had congestive heart failure within one year of treatment with doxorubicin; five of them had recurrent heart failure 3.7 to 10.3 years after completing doxorubicin treatment, and two required heart transplantation. No patient had late heart failure as a new event. CONCLUSIONS. Doxorubicin therapy in childhood impairs myocardial growth in a dose-related fashion and results in a progressive increase in left ventricular afterload sometimes accompanied by reduced contractility. We hypothesize that the loss of myocytes during doxorubicin therapy in childhood might result in inadequate left ventricular mass and clinically important heart disease in later years. CAS Registry/EC Number 23214-92-8 (Doxorubicin).

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Unique Identifier:4027874

Authors: Haq MM. Legha SS. Choksi J. Hortobagyi GN. Benjamin RS. Ewer M. Ali M.

Title: Doxorubicin-induced congestive heart failure in adults.

Source: Cancer. 56(6):1361-5, 1985 Sep 15.

Abstract: The prognosis of doxorubicin-induced congestive heart failure (CHF) is reported to be poor. To define the clinical course of doxorubicin-induced CHF, the authors reviewed their experience with 43 patients with this diagnosis. The median age of the total group was 55 years (range, 23-69); the median cumulative dose of doxorubicin was 450 mg/m2 (range, 200 mg/m2-1150 mg/m2). A majority of the patients had a diagnosis of breast cancer. The median survival of the whole group estimated by means of a Kaplan-Meier plot was 112 weeks. Twelve of 43 patients (28%) died of CHF, 7 of them (16%) because of fulminant failure in less than 8 weeks and the remaining 5 because of a more protracted course with recurrent episodes of cardiac decompensation. Twenty-five of the 43 patients (58%) achieved complete control of CHF. In the remaining 6 patients (14%), CHF had improved but was not completely controlled at the time of death, which was secondary to progressive tumor. Treatment consisted of standard therapy with digitalis and diuretics. Survival was significantly shorter in patients who presented with class IV dyspnea and in those who developed CHF less than 4 weeks after administration of the last dose of doxorubicin. The authors conclude that in a majority of patients, doxorubicin-induced CHF is easily treatable and frequently controlled with digitalis and diuretics.

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2004 Edition

Participating Faculty:  Carlos Del Rio MD  / Joyce Doyle MD / Lorenzo Difrancesco MD /  Monica Adams MD  / Josh Larned MD

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