1. Adriamycin induced cardiomyopathy G.A.Prasad MD Sinai Samaritan Medical Center Milwaukee, WI

2. Doxorubicin (Adriamycin) w Has been used in oncologic practice since the late 1960s. w The tumors most commonly responding to doxorubicin include breast and esophageal carcinomas; osteosarcoma, Kaposi's sarcoma, and soft-tissue sarcomas; and Hodgkin's and non- Hodgkin's lymphomas. w However, reports of fatal cardiotoxic effects of doxorubicin have subdued enthusiasm for this drug.

3. Incidence w In a retrospective study of 399 patient records, cardiomyopathy and congestive heart failure were dose-dependent. w Incidence rose to unacceptably high levels when the cumulative dose of the drug exceeded 550 mg per square meter of body- surface area.

4. Incidence w CHF developed in < 4 % of patients who had received a cumulative dose of 500 to 550 mg of doxorubicin /m2, < 18% at a dose of 551 to 600 mg/m2 and to about 36% at a dose of 601 mg/m2 w An empirical dose limit of 500 mg/m2 was suggested as a strategy to minimize the risk of cardiomyopathy. w CMP has been reported to develop at a cumulative dose of doxorubicin of less than 500 mg/m2.

5. Risk-Factors for Doxorubicin Induced Cardiomyopathy w Age > 70 yr w Combination therapy w Mediastinal radiotherapy (previous or concomitant) w Previous cardiac disease (coronary, valvular, or myocardial) w Hypertension w Liver disease w Whole-body hyperthermia

6. Cause ?? w The chemical structure of doxorubicin is prone to the generation of free radicals, and the oxidative stress that results correlates with cellular injury. w Doxorubicin administration is associated with a decrease in the presence of the endogenous antioxidants responsible for the scavenging of free radicals. w A decrease in antioxidants and an increase in oxidants (free radicals) result in increased oxidative stress, leading to myocardial damage.

7. Diagnosis w The standard clinical approach to monitoring for doxorubicin cardiotoxicity : assessment of base-line cardiac performance before doxorubicin therapy begins regular monitoring during treatment, and follow-up after therapy has been completed. w The insidious nature of doxorubicin-induced CMP is best observed in the transient improvement in cardiac performance after the completion of therapy, followed by the development of full-blown CMP with CHF after years of latency.

8. Diagnostic Procedures Characteristics w physical examination and history takinglack of specificity w electrocardiography: arrhythmias, flatteninglack of specificity of T-wave, prolongation of QT interval, decrease in R-wave voltage w serial echocardiography and radionuclidehigh reliability imaging: decrease in left ventricularwide use and ejection fractionavailability w angiography with radiolabeled anti-high sensitivity myosin antibodyfor cell necrosis; low specificity w angiocardiography with metaiodobenzyl-high sensitivity for guanidinemyocardial neural integrity and cardiac function low specificity w endomyocardial biopsygreatest reliability high expense

9. Echo and MUGA w One advantage of echocardiography over radionuclide imaging is that it does not expose patients to ionizing radiation. w The sensitivity of EF studies for the detection of subclinical early cardiomyopathy becomes even higher when they are combined with exercise stress testing. w Therefore, study of the EF should be part of the routine care of patients receiving doxorubicin treatment.

10. Endomyocardial Biopsy w The diagnostic test with the greatest specificity and sensitivity for doxorubicin-induced cardiomyopathy is endomyocardial biopsy. w These histologic markers are used to grade injury on a scale of 1 to 3) w A biopsy score of 2.5 or higher may be considered to indicate that doxorubicin therapy should be terminated.

11. loss of myofibrils and the vacuolization of cytoplasm characteristic of doxorubicin induced myopathy

12. Endomyocardial Biopsy w However, in patients with low-grade myocardial damage and no substantial changes in the ejection fraction at the completion of therapy, it is still possible that CHF with typical features of doxorubicin-induced cardiomyopathy will develop 4 to 20 years later. w Until we learn the full implications of the biopsy scores through long-term follow-up study, caution should be exercised when this system is used as a guide for the continuation or termination of therapy.

13. Mx: Prevention w Patients with cancer in whom symptoms of cardiomyopathy developed within the first year after doxorubicin therapy may have had an improvement in their condition during the first four years, but it subsequently deteriorated, and they died six to eight years later. w Hence prevention is of utmost importance

14. Prevention w Strategies that have been used in an attempt to prevent doxorubicin-induced CMP,include the use of doxorubicin analogues limits on the amount of drug used alternative drug-delivery methods and administration of doxorubicin in combination with cardioprotective agents. w None of these approaches have had more than limited success.

15. Doxorubicin analouges w Various analogues of anthracycline (including carminomycin, detorubicin, esorubicin, marcellomycin, quelamycin, and rodorubicin) are available. w However, none of these agents have any advantage over doxorubicin. w There are other analogues of anthracycline; (e.g., idarubicin, epirubicin). Their advantage over doxorubicin on an equimolar basis is also unclear.

16. Alternative modes of delivery w When used as a single agent, doxorubicin is administered by rapid intravenous infusion (within a 15-to-20-minute period), and the recommended dose (60 to 75 mg per square meter) is given every three weeks. w The effects of this standard rapid infusion were compared with those of continuous infusion over a six-hour period in a prospective, randomized study of doxorubicin treatment for metastatic carcinoma of the breast or ovary.

17. Alternative modes of delivery w Significantly greater decreases in the EF were detected in patients receiving the standard infusion w A reduction in cardiotoxicity was observed in patients who received an even higher dose of doxorubicin (600 mg /m2) as a continuous infusion over a period of 48 to 96 hours, as compared with those who received a median of 465 mg /m2 as a standard rapid infusion.

18. Cardioprotective agents w Administration of doxorubicin in combination with agents that would block its free-radical- mediated cardiotoxic effect, and yet not interfere with its antineoplastic effect has been another goal. w Several agents, including dexrazoxane (ICRF- 187) and amifostine, have been tried, but with limited success.

19. Cardioprotective agents w Dexrazoxane ( an iron chelating agent ) has been studied the most : has shown some reduction in incidence of acute myocardial injury but associated severe myelosuppression may interfere with antitumor activity of doxorubicin?? w Needs more study.

20. Treatment w Options similar to other cardiomyopathies: diuretics ace inhibitors beta blockers w Only curative option is heart transplantation.

21. Future prospects w Prevention of oxidative-stress injury, a complication inherent in repeated administration of doxorubicin, is an avenue worth pursuing. w Probucol, a lipid-lowering drug, is known to act as an antioxidant as well as to promote the activities of endogenous antioxidants. w Hope is offered by a recent experiment in animals in which probucol, prevented doxorubicin-induced CMP without compromising the antitumor benefits of the drug.

22. Conclusions: w Despite its dose-dependent cardiotoxic effects, doxorubicin remains in use because of its efficacy in the treatment of several types of tumors. w Its cardiotoxicity can be reduced by limiting the peak plasma concentration in each treatment with the use of a slower infusion as well as by limiting the overall cumulative dose. w Endomyocardial biopsy is expensive, but it remains the most sensitive method for early diagnosis of ensuing cardiomyopathy.

23. Conclusions: w A change in the LVEF, as determined by echocardiography or radionuclide imaging, is a very good indicator of developing CMP w Monitoring for such a change should be frequent during treatment and regular thereafter, throughout the patient's lifetime.

24. Conclusions: w According to Steinherz et al., echocardiography should be performed before every additional course of doxorubicin up to a total dose of 300 mg per square meter, given with or without concurrent radiation therapy. w MUGA scan should also be performed if the patient is receiving more than 400 mg per square meter in one course. w Echocardiography should be repeated 3, 6, and 12 months after the completion of therapy and every 2 years thereafter