Departments of 1 Oncology and 2 Clinical Physiology and Nuclear Medicine, Herlev Hospital, University of Copenhagen, Denmark
Received 28 June 2001; revised 22 November 2001; accepted 12 December 2001.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
With increasing doses the highly tumoricidal anthracycline drugs cause heart damage. Based on empirical drug limitations about 1015% of patients will develop congestive heart failure (CHF) with a mortality of 50% within 2 years on digitalodiuretic therapy alone. To avoid CHF there is a consensus recommendation that cardiac function should be monitored in close connection with anthracycline administration. As no prospective studies in a larger series have been performed, these recommendations are based on retrospective data on small numbers of patients.
Patients and methods
In a prospective, blinded observational study 120 patients with advanced breast cancer were followed before, during, and a median 3 years after treatment with epirubicin. They had 604 serial radionuclide measurements of left ventricular ejection fraction (LVEF) that were stored without calculations except in patients who developed a well-defined CHF.
Results
Anthracycline cardiotoxicity was closely correlated with the cumulative dose, with a great variability in individual susceptibility and a dramatic increase with advancing age. With a delayed onset of 3 months or more, epirubicin induced a threatening, slowly progressive deterioration of cardiac function continuing years after treatment. An actuarial estimation of 59% of the patients experienced a 25% relative reduction in LVEF 3 years after 8501000 mg/m2 of epirubicin and 20% had deteriorated into a CHF. The patients did not spontaneously regain cardiac function whereas continued therapy with a circadian angiotensin-converting enzyme inhibitor for more than 3 months caused a remarkably potent and long-lasting recovery.
Conclusions
Due to the displaced cardiotoxic manifestation, functional monitoring in close connection with anthracycline administration appears to be a poorly effective method while later monitoring is essential. Current monitoring recommendations should therefore be revised.
Key words: angiotensin-converting enzyme inhibition, anthracyclines, cardiotoxicity, free radical toxicity, radionuclide ejection fraction, recurrent breast cancer
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
End points
The primary end point was clinical CHF comprising a triplet of diagnostic criteria: exercise intolerance according to the NYHA, pulmonary congestion on chest radiograph or edema, and left ventricular dysfunction on echocardiography. Secondary end points were the degrees of subclinical cardiotoxicity given by a relative percent decline from pre-treatment LVEF values.
Statistical analysis
Median values of LVEF at various cumulative dose levels and times after chemotherapy were compared by a Wilcoxon matched-pairs signed ranks test with a display of average performance at various points of the therapeutic process. Studies of the present kind on cancer patients are, however, hampered by missing measurements either because some patients skip one or more of the planned examinations or because of premature death from cancer. Survival statistics with KaplanMeier estimates provide a tool for a graphical display and calculations of differences in risk-adjusted cumulative figures for cardiotoxicity. A cardiotoxic decline was registered if LVEF exceeded a predefined relative percent reduction from pre-treatment exceeding the inherent variation in the radionuclide cardiographic technique. This intraobserver variability was evaluated by a blind re-analysis of 357 of the 604 measurements of LVEF, including all serial hard copies from the patients who eventually developed clinical CHF by use of the BlandAltman method [16]. The mean difference was zero, and values were neatly fitted under a normal distribution curve. The standard deviations were 4 absolute LVEF units and 7.5 relative percent changes. The coefficients of repeatability were 8 absolute LVEF units [95% confidence interval (CI) 7.2 units to 8.6 units] and 15 relative percent changes [95% CI 14.2% to 16.5%, n = 295]. Subsequently only changes exceeding 15 relative percent were considered for further analysis. Curves of dose and/or time-to-cardiotoxic decline were generated with the use of KaplanMeier estimates censoring LVEF data at the last measurement. Probabilities of cardiotoxic decline were expressed as percentages. Comparison of cumulative decline distributions between subgroups was made with the log-rank test. The incidence of CHF and the probability of recovery with and without ACE inhibition were evaluated with the use of KaplanMeier estimates. SPSS statistical software for Windows (version 9) was used.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Median months and 5-year survival (actuarial percent) were 21 months and 17% following therapy with epirubicin outside protocol, 21 months and 11% following therapy with epirubicin in protocol, and 29 months and 16% for patients following combined therapy, respectively.
In the whole group of assessable patients only 16% had survived their breast cancer 5 years after recurrence.
Figure 1A illustrates the laboratory cardiotoxicity for patients without CHF. Cardiac function during the 56 months of anthracycline therapy is illustrated along the first part of the x-axis while cardiac function during follow-up is along the second part. The number of patients with a measurement of LVEF at a given time is indicated above the x-axis. In the anthracycline period, patients treated with HCD had a gradual decline of a median 7 absolute LVEF units or 11 relative percents (from 61% to 54%, P <0.001), with a further decrease to 51% in LVEF in the median 33 months during follow-up (P = 0.0219). Compared with pre-treatment LVEF values, the decline in the HCD group was significant after 23 months or 400 mg/m2 of epirubicin (P <0.001). In the LCD group, LVEF was unaffected during therapy and a minor decrease was first apparent a median of 3 months later (P = 0.0034).
|
Figure 2A shows the actuarial risk of developing CHF in the HCD group of patients censoring data at the last follow-up after terminating epirubicin therapy. Patients who died without signs of CHF were registered as being at risk. Median onset of CHF was delayed 3 months or more after terminating epirubicin therapy (1.560 months). After 1 year the risk was 11%, increasing after 2 and 5 years to 14% and 20% (95% CI 5% to 37%), respectively. The patients with a delay of 2 and 5 years before onset were also the youngest (50 and 44 years) to develop CHF. The diagnosis was confirmed by echocardiography. None of the 10 patients who developed CHF had pericardial effusion. They all had a severe reduction of wall motion in the anteroseptal and lateral regions, while the inferior wall was less affected.
|
Figure 2B illustrates the actuarial probability of recovery with and without ACE inhibition. Included for this estimation were 33 patients (30 HCD and three LCD) who had a relative fall from pre-treatment LVEF values >20% after ending epirubicin therapy, who were without symptoms, and had a subsequent measurement of LVEF without ACE inhibition. A further 18 patients (16 HCD and two LCD) had a 20% reduction in cardiac function without a subsequent measurement, indicated by the black box at zero. An event of incomplete recovery was then arbitrarily registered as a relative increase of at least 15% from the 20% reduced value. Values at the last LVEF measurement were censored. Only one of the 33 patients without ACE inhibition had a late recovery 18 months after continued treatment with a calcium antagonist contrasting with seven of the eight patients with CHF evaluable after ACE inhibition (P <0.001). In these patients, improvement occurred after a lag of a median 3 months (6 weeks to 8 months). The patient with a delay of 2 years before development of CHF needed 8 months of ACE inhibition to regain cardiac function, underlining the importance of prolonged therapy. The youngest patient (44 years at therapy) developed CHF after a delay of 5 years and regained cardiac function after 2 months of ACE inhibition, after which she obtained a better functional performance than in the preceding 3 years. Three patients discontinued ACE inhibitor therapy, after 21, 28 and 28 months, with a marked decline of 1013 LVEF units after 45 months (Figure 1B). Only one patient with CHF survived from breast cancer for more than 5 years. Despite continued ACE inhibition with stable LVEF values she had a decline in LVEF from 50 to 30% after 5 years. The study was performed in the pre-taxane era. Extensive second-line therapy with HCDs of 4060 g cyclophosphamide was used for treatment of recurrent disease in three patients treated with ACE inhibition for CHF without promoting cardiotoxicity.
In Figure 3, the time of first appearance of a decline in LVEF exceeding 15, 20, 25, 30 and 35% from baseline in the HCD group is plotted by means of KaplanMeier estimates. For the LCD group only the 25% decline curve is plotted, illustrating no events of this severity at this low dose level in the observation period contrasting an actuarial risk of 59% (28 of 85) in the HCD group (P <0.001). As the LCD group of patients was otherwise comparable to the HCD group (Table 1), the cardiotoxicity could be ascribed to epirubicin and not the breast cancer disease state of the patient. The top curves show that a reduction of 15% from baseline occurred in 50% (40 of 85) of the patients during and 30% (19 of 85) following termination of chemotherapy, yielding an actuarial risk of 80% (59 of 85). Bars indicate the remaining 20% (26 of 85) of the patients who are still at risk, having sustained no changes in LVEF greater than or equal to 15%. The cumulative iso-cardiotoxic decline curves constructed at various levels only take one measurement from each patient into account, either the first time a given reduction was exceeded or the last measurement of LVEF in the patient at risk for such a reduction. The actuarial risk of a 20% iso-cardiotoxic decline in the HCD group was 78%, almost double that of 44% in the LCD group (curve not shown, P = 0.0022), indicating linearity between the degree of cardiotoxicity and the cumulative dose. The difference between the high- and low-dose groups was seen at all levels but was most manifest with increasing cardiotoxic affection. Both groups had a remarkable gap between the cumulative iso-decline curves for a 20% and 25% reduction in cardiac function. The most susceptible HCD patients showed a 20% reduction in cardiac function 23 months after starting epirubicin therapy at a cumulative dose of 400 mg/m2. The double time and dose was necessary for the first HCD patients to have a 25% decline in cardiac function. Thirty-five percent of the HCD patients (27 of 85) had a 20% reduction in cardiac function during chemotherapy, while this was the case for only 15% of patients with a 25% reduction (11 of 85). An increase in the cumulative iso-cardiotoxic decline level by 5% each time halved the number of declines occurring during chemotherapy. The more severe the functional cardiotoxic decline, the longer the interval before its expression. Even years after ending epirubicin administration, a few patients had a retarded deterioration of cardiac function exceeding a 20% reduction. Almost all events (11 of 12) of the most severe reduction in cardiac function (35% reduction) took place in the post-anthracycline period. Figure 3 also illustrates the wide variability among the individual patients in their susceptibility to the cardiotoxic effects of anthracyclines. Forty-one percent of the patients did not experience a 25% relative reduction from baseline, and 20% did not even experience a 15% reduction. This difference in susceptibility is also evident from the wide range around the median before, during and after epirubicin therapy in both the HCD and LCD groups, and in patients with or without CHF as illustrated in Figure 1A and B.
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In two major consensus guidelines for monitoring anthracycline cardiotoxicity [12, 13], radionuclide LVEF estimations were proposed as prognostically valuable during therapy, with long-term progression recorded at least 1014 days after the last anthracycline dose [13].
These recommendations are based on mostly retrospective data with a substantial lack of data on dysfunction in the post-anthracycline period [3, 14, 17]. Before the present study, two retrospective studies from our institute had demonstrated that radionuclide measurements of LVEF during anthracycline therapy were unable to predict the development of CHF [5, 6]. Those and similar reports [3, 14, 15] provided the ethical basis for the present study. We serially recorded LVEF during and after anthracycline therapy but only made estimations in those cases where the patients manifested clinical signs of cardiotoxicity. Results were stored for analyses at least 6 months after terminating epirubicin therapy for the last included patient without premature interference from laboratory data. The present study is the first with blinded, observational, prospective collected data that demonstrate a displacement of the functional cardiotoxic effect. The lag-time necessary for anthracycline-induced subclinical processes to express functional cardiac manifestation makes the radionuclide method insensitive and unable to predict outcome when monitoring is performed in close connection to anthracycline administration. Recording of cardiotoxicity by LVEF months to years after anthracycline administration is a much more meaningful end point for a monitoring program. Current guidelines and recommendations should therefore be revised, as proposed by others [3, 6, 14].
The cardiotoxic effects of the anthracycline anthraquinone have been consistently associated with free radical generation [3, 4, 19, 20]. Patients treated with anthracyclines may serve as a model for studying the pathophysiological processes of anthraquinone free radical-induced damage in the healthy intact human heart, providing us with the rare opportunity to analyze the time windows for these functional damages. Anthracycline-induced cardiotoxicity resembles the cardiotoxicity caused by the burst of free radical formation after activated phagocytic activity following myocardial infarction, or after re-oxygenation and reperfusion of ischemic tissue following thrombolytic therapy or other revascularization procedures [2128]. Smoking similarly causes a severe oxidative stress, with the principal radicals being anthraquinones held in the tarry matrix [29] that increase the risk of cardiovascular disease, especially in women [30]. Female sex is in general associated with a remarkable, about two-fold, increase in cardiac morbidity and mortality once a cardiac risk factor is established [9]. This increase in female susceptibility is observed after anthracycline therapy [11, 15] and thrombolytic therapy [26], in diabetes [10], with cigarette smoking [7, 30] and during aging [7]. In the present study of female patients we found age to be the most dominant factor, increasing anthracycline cardiotoxicity susceptibility. The same age-dependent increase in susceptibility to heart damage is seen in idiopathic, dilated cardiomyopathy [8], CHF of other causes [7, 10], and after thrombolytic therapy [26, 27]. The normal senescent heart is potentially a diseased heart [31]. It has been suggested that many of the aging processes themselves are the result of long-sustained tissue abuse by free radicals [23] with a reduced amount of protective antioxidants in the old and the sick [27].
The cardiac matrix is profoundly disrupted in patients with advanced heart failure [32], after reperfusion in the stunned myocardium [33] or after anthracycline administration [34, 35], as also demonstrated by the histological section from our patient who died of a dilated CHF. Increased dilatation with decreased LVEF correlates well with adverse prognosis in idiopathic dilated cardiomyopathy, in CHF, after thrombolysis, after myocardial infarction, and in anthracycline cardiomyopathy [2, 7, 8, 10, 26, 36]. A common property of cardiac toxicity associated with cardiac matrix alterations, including anthracycline cardiotoxicity, is the salutary effect of prolonged ACE inhibition [3, 2326, 3739]. Without ACE inhibition the prognosis of anthracycline-induced CHF is grave [1, 2, 5, 6], resembling the general prognosis of CHF and idiopathic cardiomyopathy with a mortality rate of about 50% within 2 years of diagnosis [1, 710]. In our institute we have previously performed two retrospective studies on the incidence and outcome of CHF after therapy with 1000 mg/m2 or more of epirubicin for advanced breast cancer [5, 6]. In one study of 135 patients, the incidence of CHF was 35% and four of seven patients died of CHF [6]. In another study of 469 patients, 15% developed CHF with a mortality of 40% within a median of 5 months [5]. Results from this study made us recommend a reduced maximum cumulative dose of epirubicin of 900 mg/m2. In the present prospective study with ACE inhibition only 1 of 10 patients with severe heart failure (NYHA class IIIIV) died of CHF. The patients with a decreased cardiac function did not spontaneously recover during the observation period but function could only be reversed by ACE inhibition for several months. We have now successfully treated a total of more than 60 patients with severe CHF after anthracycline therapy with ACE inhibition, with a remarkably long-lasting recovery evaluated clinically and by LVEF determination. All three patients in the present study who stopped ACE inhibition after years of stabilized cardiac function deteriorated. This corresponds to trials with ACE inhibition documenting the necessity of ACE inhibitor therapy lasting years in heart failure [38, 39], and this should probably also should be the case after anthracycline-induced CHF.
The lag time before progressive cardiac deterioration with dilatation occurs may, however, open a therapeutic window for interventional strategies. We have performed and are awaiting results from a placebo-controlled blinded study for prevention of cardiotoxicity in the post-anthracycline period by ACE inhibition.
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Haq MM, Legha SS, Choksi J et al. Doxorubicin-induced congestive heart failure in adults. Cancer 1985; 56: 13611365.[ISI][Medline]
3.
Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996; 125: 4758.
4.
Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998; 339: 900905.
5. Ryberg M, Nielsen D, Skovsgaard T et al. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol 1998; 16: 35023508.[Abstract]
6. Nielsen D, Jensen JB, Dombernowsky P et al. Epirubicin cardiotoxicity: a study of 135 patients with advanced breast cancer. J Clin Oncol 1990; 8: 18061810.[Abstract]
7. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285: 14411446.[ISI][Medline]
8. Fuster V, Gersh BJ, Giuliani ER et al. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981; 47: 525531.[ISI][Medline]
9. Wilson JR, Schwartz JS, Sutton MS et al. Prognosis in severe heart failure: relation to hemodynamic measurements and ventricular ectopic activity. J Am Coll Cardiol 1983; 2: 403410.[ISI][Medline]
10. Smith WM. Epidemiology of congestive heart failure. Am J Cardiol 1985; 55: 3A8A.[Medline]
11.
Lipshultz SE, Lipsitz SR, Mone SM et al. Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 1995; 332: 17381743.
12. Steinherz LJ, Graham T, Hurwitz R et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 1992; 89: 942949.[Abstract]
13. Ritchie JL, Bateman TM, Bonow RO et al. Guidelines for clinical use of cardiac radionuclide imaging. Report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Committee on Radionuclide Imaging), developed in collaboration with the American Society of Nuclear Cardiology. J Am Coll Cardiol 1995; 25: 521547.[ISI][Medline]
14. Lipshultz SE, Sanders SP, Goorin AM et al. Monitoring for anthracycline cardiotoxicity. Pediatrics 1994; 93: 433437.[Abstract]
15. Krischer JP, Epstein S, Cuthbertson DD et al. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol 1997; 15: 15441552.[Abstract]
16. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 307310.[ISI][Medline]
17. Lipshultz SE, Colan SD, Gelber RD et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991; 324: 808815.[Abstract]
18. Steinherz LJ, Steinherz PG, Tan CT et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. J Am Med Assoc 1991; 266: 16721677.[Abstract]
19. Myers CE, McGuire WP, Liss RH et al. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 1977; 197: 165167.[ISI][Medline]
20. Bachur NR, Gordon SL, Gee MV. A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res 1978; 38: 17451750.[ISI][Medline]
21. Thompson JA, Hess ML. The oxygen free radical system: a fundamental mechanism in the production of myocardial necrosis. Prog Cardiovasc Dis 1986; 28: 449462.[ISI][Medline]
22. Belch JJ, Bridges AB, Scott N, Chopra M. Oxygen free radicals and congestive heart failure. Br Heart J 1991; 65: 245248.[Abstract]
23. Cross CE, Halliwell B, Borish ET et al. Oxygen radicals and human diseases. Ann Intern Med 1987; 107: 526545.[ISI][Medline]
24. Bolli R, Jeroudi MO, Patel BS et al. Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. Proc Natl Acad Sci USA 1989; 86: 46954699.[Abstract]
25. Bulkley GB. Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function. Lancet 1994; 344: 934936.[ISI][Medline]
26. Stevenson R, Ranjadayalan K, Wilkinson P et al. Short and long term prognosis of acute myocardial infarction since introduction of thrombolysis. Br Med J 1993; 307: 349353.[ISI][Medline]
27. Landray MJ, Nuttall SL, Lydakis C et al. Oxidative stress after thrombolysis. Lancet 1998; 352: 960.[ISI][Medline]
28. Davies SW, Underwood SM, Wickens DG et al. Systemic pattern of free radical generation during coronary bypass surgery. Br Heart J 1990; 64: 236240.[Abstract]
29. Church DF, Pryor WA. Free-radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect 1985; 64: 111126.[ISI][Medline]
30.
Prescott E, Hippe M, Schnohr P et al. Smoking and risk of myocardial infarction in women and men: longitudinal population study. Br Med J 1998; 316: 10431047.
31. Swynghedauw B, Besse S, Assayag P et al. Molecular and cellular biology of the senescent hypertrophied and failing heart. Am J Cardiol 1995; 76: 2D7D.[Medline]
32. Weber KT, Pick R, Janicki JS et al. Inadequate collagen tethers in dilated cardiopathy. Am Heart J 1988; 116: 16411646.[ISI][Medline]
33. Zhao MJ, Zhang H, Robinson TF et al. Profound structural alterations of the extracellular collagen matrix in postischemic dysfunctional (stunned) but viable myocardium. J Am Coll Cardiol 1987; 10: 13221334.[ISI][Medline]
34. Dardir MD, Ferrans VJ, Mikhael YS et al. Cardiac morphologic and functional changes induced by epirubicin chemotherapy. J Clin Oncol 1989; 7: 947958.[Abstract]
35. Caulfield JB, Bittner V. Cardiac matrix alterations induced by adriamycin. Am J Pathol 1988; 133: 298305.[Abstract]
36. White HD, Norris RM, Brown MA et al. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987; 76: 4451.[Abstract]
37. Jensen BV, Nielsen SL, Skovsgaard T. Treatment with angiotensin-converting-enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. Lancet 1996; 347: 297299.[ISI][Medline]
38. Jensen BV, Nielsen SL. Losartan versus captopril in elderly patients with heart failure. Lancet 1997; 349: 1473.
39. Flather MD, Yusuf S, Kober L et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355: 15751581.[ISI][Medline]