Anthracycline &Cardiotoxicity:

1. Anthracycline &Cardiotoxicity: Dr. Florence Morriello Critical Care Medicine Cardiology Grand Rounds The Toronto General Hospital University of Toronto

2. Case Report • A 47 y/o woman presented with progressive fatigue and pancytopenic • PMH significant for ovarian carcinoma s/p hysterectomy and oopherectomy, HTN and DM • BM biopsy performed which showed AML-M2 received induction chemotherapy with cytarabine, daunorubicin, and etopside. • MUGA prior to therapy showed an ejection fraction of 64%

3. Case Report • She achieved remission • Six months later presented with febrile neutropenia. Clinically found to be in severe congestive heart failure and hemodynamically unstable requiring inotropic support. Her counts were normal and she no evidence of active leukemia. • Work upshowed a dilated cardiomyopathy with an EF of 15%, as per TTE

4. Cardiotoxicity associated with Chemotherapy • Anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, anthraquinone mitoxantrone) • cause irreversible and sometimes fatal cardiomyopathy

5. INTRODUCTION TO ANTHRACYCLINES • Athracyclines were originally isolated from Streptomyces peucetius for use as cytotoxic antibiotics. • found to have broad anti-tumor activity –first line for hematological and solid tumors • Inhibit DNA and RNA synthesis & prevent DNA repair by action on topoisomerase II

6. MECHANISM OF CARDIOTOXICITY • production of toxic oxygen free radicals • accumulate in the heart because of the high levels of cardiolipin • Cardiac tissue limited capacity to deal with free radicals (because of low levels of antioxidant enzymes)

7. MECHANISMS OF CARDIOTOXICITY • cause lipid peroxidation of membranes, leading to vacuolation, irreversible damage, and myocyte replacement by fibrous tissue • also associated with a decrease of the endogenous antioxidant enzymes, such as glutathione peroxidase (responsible for the scavenging of free radicals) • Mitochondria are particularly susceptible to free radical damage

8. MECHANISMS OF CARDIOTOXICITY • Apoptosis • Elevated calcium accumulation in mitochondria • Modulation of cardiac gene expression Zucchi. Curr Med Chem Anti-Canc Agents. 3:151, 2003

9. MECHANISMS OF CARDIOTOXICITY

10. RISK FACTORS • strongest predictor is cumulative dose • age over 70 • Prior irradiation • concomitant administration of other chemotherapeutic agents • concurrent chest irradiation • underlying heart disease are also important

11. CUMULATIVE DOSE • Von Hoff et al. reviewed reports on 5,613 patients receiving daunomycin noted two distinct patterns of cardiotoxicity: congestive heart failure (cardiomyopathy) and electrocardiographic changes. • a dose-response relationship between the total dose of daunomycin and the development of cardiomyopathy, both in children and adults.

12. CUMULATIVE DOSE • Early reports cumulative doxorubicin doses of 400, 550, and 700 mg/m2 the percentage of patients who developed cardiotoxicity was 3, 7, and 18 percent, respectively • Recommended doxorubicin treatment be stopped empirically in all patients at a cumulative total dose <550 mg/m2

13. AGE • Age extremes • UNclear whether preexisting heart disease increases susceptibility to anthracycline-induced damage

14. PATHOLOGICAL CHANGES • Autopsy studiescardiac injury is patchy and at times may be limited to one ventricle or to just one or more walls within a ventricle • Such patchy involvement may impose limitations on diagnosis by endomyocardial biopsy

15. PATHOLOGICAL CHANGES Adriamycin cardiotoxicity. Myocyte in center (‘adria cell') shows extensive pale areas of loss of myofibrils and fragmentation of myofilaments. Mitochondria (dark oval structures in same areas) are not qualitatively altered. Remnants of Z bands form a diagonal dense area in center.

16. PATHOLOGICAL CHANGES Compare transverse section of normal cardiac myocyte (upper left) with myocyte severely affected by adriamycin (lower right). There is complete disorganization of sarcomeres and extensive fragmentation of myofilaments. Mitochondria are small (compare with top). Remnants of Z bands are present near right edge. This complete loss of contractile elements in one myocyte with preservation of the adjacent cell creates sharply defined amphophilic or basophilic areas that characterize ‘adria cells’ in paraffin sections. (×8200; courtesy of Dr LF Fajardo, Stanford, CA)

17. CLINICAL MANIFESTATIONS • The clinical manifestations of anthracycline cardiotoxicity depend in part upon their temporal relationship to treatment • Acute VS Chronic.

18. Acute Toxicity • Occur with or immediately following administration and are usually transient • Electrocardiographic abnormalities • increase in plasma brain natriuretic peptide (a marker of increased cardiac filling pressures and heart failure) • Pericarditis/myocarditis

19. How is the cardiotoxicity manifested? • The chronic toxicityprimarily destruction of myocytes leading to congestive failure • The cardiomyopathy is irreversible. • It is more common than the acute toxicities.

20. Chronic Toxicity • The peak time for the appearance of symptoms of heart failure was three months after the last anthracycline dose • Onset of symptomatic heart failure can occur more than a decade after the last anthracycline dose • is common in survivors of childhood malignancy, in whom late heart failure is due to a nonischemic dilated cardiomyopathy

21. REDUCING THE RISK • use of altered administration schedules • development of structural analogs • liposome encapsulation of the anthracycline molecule • use of adjunctive cardioprotective agents. • Intensive monitoring has been used to detect the earliest evidence of cardiotoxicity and prevent the development of more severe heart failure.

22. ALTERED SCHEDULES OF DRUG ADMINISTRATION • Decrease the risk of cardiotoxicity while maintaining efficacy • Observational study showed a potential benefit in 14 of 30 patients receiving conventional bolus treatment (median cumulative dose of 465 mg/m2) compared with 2 of 21 treated with prolonged infusions (median cumulative dose of 600 mg/m2) • (Mackay et al. Ann Intern Med 1982)

23. ALTERED DRUG ADMINISTRATION • A similar benefit was not observed, however, in a randomized trial in 121 children treated with 360 mg/m2 for acute lymphoblastic leukemia • the mean left ventricular fractional shortening decreased by a similar amount with either bolus or 48 hour infusion (Lipshultz et al. J Clin Oncol. 2002)

24. ALTERED DRUG ADMINISTRATION • Two randomized trials have evaluated a shorter, six-hour infusion of doxorubicin: • In one trial: 69 patients treated with adjuvant doxorubicin for soft tissue sarcoma • The 6-hour infusion was associated with a lower incidence of cardiotoxicity, which was defined as a ≥10 percent reduction in LVEF (42 percent at a median infusion dose of 540 mg/m2 versus 61 percent at a median total dose of 420 mg/m2 with bolus therapy) • Howevera trend toward an increased rate of metastasis and higher rate of death with infusion therapy

25. ALTERED DRUG ADMINISTRATION • A second trial studied women with breast or ovarian cancer, results also suggested a decreased incidence of cardiotoxicity with a 6-hour infusion (Shapira et al. Cancer 1990) • most doxorubicin is still administered via bolus therapy • prolonged infusion with doxorubicin-based regimens have demonstrated efficacy, the frequent need for hospitalization and placement of a central venous catheter makes this approach less attractive to patients and less cost effective

26. STRUCTURAL ANALOGUES • Dexrazoxane is an oral iron chelator • It prevents the formation of the semiquinone-iron which leads to reactive oxygen production • adverse reactions: myelosuppression, pain at injection site, and phlebitis

27. DEXRAZOXANE • Some data suggests that dexrazoxane may decrease response to chemotherapy • One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group. • There has been no difference in overall survival or progression free survival in this trial

28. Dexrazoxane and Cardiotoxicity • In 2 randomized controlled trials performed in metastatic breast cancer, 289 patients being treated with Anthracyclines and 249 were Anthracyclines + dexrazoxane. • Symptomatic CHF developed in 8% of the placebo group versus 1% of the dexrazoxane group

29. Liposomal preparations of anthracyclines • Liposomal preparations –preferentially taken up by tissues enriched in phagocytic reticuloendothelial cells • In a retrospective analysis of 8 phase I and II clinical trials, no clinically significant decrease in EF was found in 41 patients treated with 500 mg/m2

30. GUIDELINES FOR MONITORING ANTHRACYCLINE TREATMENT • Perform baseline radionuclide angiocardiography at rest for calculation of LVEF prior to treatment • Subsequent studies are performed at 3 weeks after the indicated total cumulative doses have been given • Patients with normal baseline LVEF ( 50 percent) • Perform a second study after 250 to 300 mg/m2 • Repeat study after 400 mg/m2

31. GUIDELINES FOR DOXORUBICIN • Doxorubicin therapy should not be initiated with baseline LVEF 30 percent • In patients with LVEF >30 percent and <50 percent, sequential studies should be obtained prior to each dose • Discontinue doxorubicin with cardiotoxicity: absolute decrease in LVEF 10 percent (EF units) and/or final LVEF 30 percent. • Schwartz, RG, McKenzie, WB, Alexander, J, et al, Am J Med 1987; 82:1109.

32. GUIDELINES FOR DOXORUBICIN • Patients with known heart disease, radiation exposure, abnormal EKG, or cyclophosphamide therapy; or after 450 mg/m2 in the absence of any these risk factors, perform sequential studies thereafter prior to each dose • Discontinue doxorubicin therapy once functional criteria for cardiotoxicity develop, eg, absolute decrease in LVEF 10 percent (EF Units) associated with a decline to a level of 50 percent (EF Units)

33. USE OF CARDIOPROTECTIVE AGENTS: Carvedilol • Animal studies have suggested that concurrent administration of the beta blocker carvedilol may protect against the cardiotoxicity of anthracyclines • Matsui H et al. showed that Carvedilol protects against DOX-induced cardiomyopathy and that this effect may be attributed to the antioxidant and lipid-lowering properties of CARVEDILOL, not to its beta-blocking property.

34. Carvedilol • Santos et al. concluded that carvedilol may have a significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients. • Spallarossa et al. found that carvedilol is potentially protective against doxorubicin cardiotoxicity by decreasing free radical release and apoptosis in cardiomyocytes

35. Significant Improvement in EF After Optimal HF Therapy Percent of Patients LVEF Decrease After Chemo EF Improved After Optimal Treatment HF with Normal EF Lenihan et al, HFSA 2008

36. ACE INHIBITORS • Although the data are limited, these results are consistent with the use of ACE inhibitors as first-line therapy for both asymptomatic left ventricular dysfunction and overt heart failure due to systolic dysfunction

37. Recovery of LV dysfunction with standard HF therapy Jensen, et al. Annals of Oncology. 2002. 13:499-709.

38. ACE Inhibition appears quite important for prevention of toxicity Cardinale D et al. Circulation. 2006;114:2474-2481

39. VALSARTAN • In a small randomized trial by Nakamae et al, the angiotensin II receptor blocker valsartan blocked all of the acute effects of anthracycline treatment. • 40 consecutive patients with untreated non-Hodgkin lymphoma who were scheduled to undergo standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) (mean age, 56 yrs; range, 24-70 yrs) were randomized to receive CHOP with or without 80 mg/day of valsartan • Nakamae et al., Cancer 2005

40. VALSARTAN • CHOP induced transient increases in the left ventricular end-diastolic diameter in an echocardiogram, the QTc interval and elevated plasma brain and atrial natriuretic peptides • All these changes returned to nearly normal levels within a week after CHOP (P < 0.001). • valsartan significantly prevented all these changes except for the elevation in atrial natriuretic peptide (P < 0.05). No significant change was observed in blood pressure or heart rate between the valsartan and control groups.

41. MONITORING • Cardiac biomarkersSerum troponins • Brain natriuretic peptide • Endomyocardial biopsy • ECHOCARDIOGRAPHY AND RADIONUCLIDE ANGIOGRAPHY • Cardiac MRI

42. Troponin I is valuable in detecting Cardiotoxicity Cardinale et al. Circ. 2004;109:2749-2754

43. Detecting CardiotoxicitySummary of current methods • The guidelines* at present suggest a baseline EF measurement and a repeat study at some time interval (keep in mind that more than 1/3 of patients with heart failure have a normal EF and their prognosis is similar to those with systolic dysfunction) • Symptoms are the mainstay of the diagnosis of heart failure (and the utility of that is in question) • No recommendation for biomarker testing or preventive therapy *AHA,ACC,HFSA, and ASCO websites

44. Prevention • Minimize athracycline dose • Use different dosing schedules • Use different forms of athracyclines that cause less cardiotoxicity • Use agents to prevent the cardiotoxicity

45. Future directions • Further evaluation of current agents • Statins • ACE inhibitors

46. REFERENCES Seymour et al. Use of dexrazoxane as a cardioprotectant in patients receiving doxorubicin or epirubicin chemotherapy for the treatment of cancer. Cancer PrevControl 3(1999), pp. 145–159. Shapira et alia, Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation.Cancer 65 (1990), pp. 870 -873. P.K. Singal, Doxorubicin-induced cardiomyopathy. NEJM 339 (1998), pp. 900- 905 Speyer et al. Prospective evaluation of cardiotoxicity during a six-hour doxorubicin infusion regimen in women with adenocarcinoma of the breast . American Journal of Medicine78 (1985), pp. 555-563. Dalen et al. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2005;(1):CD003917. Gabizon, Lyass O, Berry G. Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies. Cancer Invest 2004;22(5):663-9.

47. REFERENCES Andreopoulou E; Gaiotti D; Kim E; Downey A; Mirchandani D; Hamilton A; Jacobs A; Curtin J; Muggia F SO. Pergylated liposomal doxorubicin HCL: Experience with long-term maintenance in responding patients with recurrent epithelial ovarian cancer. Ann Oncol. 2007 Apr;18(4):716-21. Epub 2007 Feb 13. S. Jeffers et al., Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann. Oncol.11 (2000), pp. 1029–1033. S.S. Legha et alia, Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96 (1982), pp. 133-139. K.J. Schimmel et alia, Cardiotoxicity of cytotoxic drugs. Cancer Treatment Reviews 30 (2004), pp. 181-191. S.M. Swain et alia, Cardioprotection with dexrazoxane for doxorubicin- containing therapy in advanced breast cancer. J Clin Oncol 15 (1997), pp. 1318–1322.

48. REFERENCES S.M. Swain et alia, The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review. J Cancer Res Clin Oncol 130 (2004), pp. 1-7. Legha, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Annn Intern Med 1982 Feb;96(2):133-9.   Lipshultz, et al. Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. J Clin Oncol. 2002 Mar 15;20(6):1677-82 Casper et al. A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and an analysis of prognostic factors. Cancer 1991 Sep 15;68(6):1221-9.

49. REFERENCES • Cardioprotective interventions for cancer patients receiving anthracyclines. AU Dalen E; Caron H; Dickinson H; Kremer L SO Cochrane Database Syst Rev 2005;(1):CD003917 • Diminishment of respiratory sinus arrhythmia foreshadows doxorubicin-induced cardiomyopathy. AU Hrushesky WJ; Fader DJ; Berestka JS; Sommer M; Hayes J; Cope FO SO Circulation 1991 Aug;84(2):697-707k sufficient evaluation . • Early detection of anthracycline induced cardiotoxicity in asymptomatic patients with normal left ventricular systolic function: autonomic versus echocardiographic variables. AU Tjeerdsma G; Meinardi MT; van Der Graaf WT; van Den Berg MP; Mulder NH; Crijns HJ; de Vries EG; van Veldhuisen DJ SO Heart 1999 Apr;81(4):419-23. • Anthracycline cardiotoxicity in children. AU Kremer LC; Caron HN SO N Engl J Med 2004 Jul 8;351(2):120-1. • Doxorubicin-induced cardiomyopathy. AU Singal PK; Iliskovic N SO N Engl J Med 1998 Sep 24;339(13):900-5.