Download Functional monitoring of anthracycline cardiotoxicity: a prospective

Original article
Annals of Oncology 13: 699–709, 2002
DOI: 10.1093/annonc/mdf132
Functional monitoring of anthracycline cardiotoxicity:
a prospective, blinded, long-term observational study of
outcome in 120 patients
B. V. Jensen1*, T. Skovsgaard1 & S. L. Nielsen2
Departments of 1Oncology and 2Clinical Physiology and Nuclear Medicine, Herlev Hospital, University of Copenhagen, Denmark
Received 28 June 2001; revised 22 November 2001; accepted 12 December 2001
Background: With increasing doses the highly tumoricidal anthracycline drugs cause heart damage.
Based on empirical drug limitations about 10–15% of patients will develop congestive heart failure
(CHF) with a mortality of ∼50% within 2 years on digitalo–diuretic 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 850–1000 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
The anthracycline semiquinone doxorubicin and the stereoisomer epirubicin are among the most effective and widely
used anti-cancer drugs with particularly widespread use in the
therapy of breast cancer, sarcomas and leukemia. Their use,
however, is limited by the risk of a delayed, life-threatening,
dilatory congestive heart failure (CHF), an unexpected sideeffect first reported by Lefrak et al. in 1973 [1]. Recovery from
anthracycline-induced CHF on digitalo–diuretic therapy alone
seldom occurs [1–5]. Mortality of patients deteriorating into
New York Heart Association (NYHA) class III–IV exceeds
*Correspondence to: Dr B. V. Jensen, Department of Oncology, Herlev
Hospital, University of Copenhagen, DK-2730 Herlev, Denmark.
Tel: +45-4635-9577; Fax: +45-4635-9593; E-mail: [email protected]
© 2002 European Society for Medical Oncology
50% within 2 years [1, 2, 5, 6], resembling the general prognosis of CHF and idiopathic cardiomyopathy [7–10]. A rapidly
growing number of people, including an alarming fraction of
the 150 000 or more adults in the USA who have survived
childhood cancer, will have substantial morbidity and mortality because of anthracycline-related cardiac disease, calling
for effective protection and therapy [3, 11]. This grave prognosis has led to recommendations of extensive and expensive
functional monitoring programs during anthracycline treatment to identify high-risk patients [4, 12, 13]. In the guidelines
from the Cardiology Committee of the Children’s Cancer
Study Group [12], the American College of Cardiology, the
American Heart Association and the American Society of
Nuclear Cardiology [13], radionuclide angiographic measurement of ventricular function is recommended during anthracycline therapy timed 10–14 days after the last dose.
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They state that it is safe to continue therapy if the left ventricular ejection fraction (LVEF) remains above the lower limit of
normal, and that if the LVEF becomes subnormal and anthracycline therapy is discontinued LVEF usually stabilizes at that
point. These statements, however, are mostly based on retrospective data limited by a relatively small number of patients
[3, 14], factors that may confound the concept of monitoring
efficacy and the accuracy of clinical predictions. Review of
the data on which these recommendations were based has
raised doubt about the reliability and sensitivity of monitoring
of the ejection fraction for identification of early cardiotoxicity
[14, 15]. There has therefore been a strong call for prospective, blinded data in a larger series [3, 14]. Based on our
previous experience of anthracycline cardiotoxicity lacking
predictability for development of CHF by radionuclide
monitoring [5, 6], we performed a prospective, blinded, observational study on the time windows for developing anthracycline-induced cardiotoxicity. The majority of patients were
allocated to treatment with a high cumulative dose (HCD) of
1000 mg/m2 epirubicin and a smaller control group to a low
cumulative dose (LCD) of 500 mg/m2. The final end points
were the clinical development of CHF and the degrees of
subclinical cardiotoxicity evaluated by close functional
monitoring of radionuclide-estimated LVEF before and during
more than 3 years of follow-up.
Patients and methods
Patients with their first sign of recurrent metastatic breast cancer were
referred for first-line anthracycline-based therapy. Inclusion criteria were:
prior chemotherapy limited to one regimen without anthracyclines; age
18–65 years; WHO performance status <3 and a life expectancy greater
than 3 months, adequate hematological, hepatic and renal function; and no
history of severe heart failure or myocardial infarction. All patients referred
to our department between June 1991 and November 1993 satisfying the
above criteria were asked to participate. At initiation of the monitoring
program all patients had monotherapy with epirubicin, aiming at an
HCD not exceeding 1000 mg/m2. After inclusion of the first 40 patients,
54 patients entered a randomized investigation of either HCD monotherapy with epirubicin every third week, or epirubicin every 6 weeks
alternating with four courses of cyclophosphamide (3 g/m2 per course)
corresponding to an LCD of epirubicin 500 mg/m2. In this period,
26 patients refused randomization and had monotherapy leaving 92 HCD
patients (Table 1). Epirubicin was administered as a 5-min infusion of
130 mg/m2. Radionuclide cardiography of the LVEF was performed after
intravenous injection of 1000 MBq human serum albumin 99mTc. Beside
pre-treatment evaluation, the history and clinical evaluation were repeated
before each dose of epirubicin and ECG, chest X-ray, measurement of
LVEF before and after 500, 780, 900 and 1000 mg/m2 and 1, 3, 6 and a
median 33 months later, or when it was considered necessary from the
clinical status. Patients in the LCD regimen had their second measurement
of LVEF 1.5 months after the last epirubicin injection.
During the investigation period, hard copies of LVEF data were stored
without calculations of LVEF. Six months after the last included patient
had terminated epirubicin therapy, all serial hard-copied LVEF data from
each patient were analyzed by one of three skilled technicians. The mean
of three measurements not deviating by more than 5 units from each other
was used from each examination. If a patient developed clinical signs of
CHF, however, the treating doctor could demand determination of LVEF
in order to confirm an echocardiographic diagnosis of left ventricular
dysfunction. In the case of progressive deterioration of CHF on digitalo–
diuretic therapy, angiotensin-converting enzyme (ACE) inhibition with a
long-acting circadian ACE inhibitor was initiated. The local Ethics Committee approved the study, and informed, written consent was required.
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 Kaplan–Meier 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 Bland–Altman 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 Kaplan–Meier 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 Kaplan–Meier estimates. SPSS statistical software for
Windows (version 9) was used.
Results
Table 1 gives the clinical characteristics of the patients.
Thirteen included patients were not assessable for cardiotoxicity, 11 because of early death, and two because they
refused further examinations (one HCD and one LCD). No
patients in the LCD group developed CHF compared with
10 patients in the HCD group with NYHA class III–IV, cardiomegaly, pleural effusion and/or lung stasis on chest X-ray, and
weight gain. They were slightly older (P = 0.05) with lower
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Table 1. Characteristics of patients (values followed by parentheses are medians with ranges)
High cumulative dose (HCD)
Low cumulative dose (LCD)
(28 patients registered;
22 assessable)
(26 patients registered;
66 treated outside protocol;
85 assessable)
Clinical cardiotoxicity (n)
None (75)
CHF (10)
None (22)
a
53 (36–59)
Age at start of epirubicin (years)
50 (29–65)
54 (44–62)
LVEF before epirubicin therapy (%)
61 (45–75)
53 (45–61)b
59 (50–68)
Performance status at inclusion (0/1/2)
56/17/2
8/2/0
15/4/3
None
30
4
4
Tamoxifen
8
2
5
CMF
12
2
6
Irradiation (left/right side)
11/5
0/2
2/1
CMF and irradiation (left/right/bilateral)
5/4/0
0/0/0
2/0/2
35/9/31
7/0/3
12/3/7
Cumulative cyclophosphamide (g/m )
–
–
8.7 (7.3–10)
Cumulative epirubicin (mg/m2)
1000 (360–1000)
1000 (850–1000)
500 (386–623)
360–830
11
0
22
850–950
11
2
–
1000
53
8
–
8 (4–12)
8 (7–11)
4
4
7
0
22
6–7
4
2
–
8
45
4
–
9–12
19
4
–
5.1 (2–8)
5.2 (4.3–8)
4.8 (4.2–6.1)
Before and during epirubicin therapy
254
32
28
Following epirubicin therapy
160
60
70
21 (3–84)
36 (15–80)
29 (3–78)
Prior therapy
Smoking habits (never/former/current)
2
Number of epirubicin treatments
Months of epirubicin treatment
No. of LVEF measurements (n = 604)
Survival in months after start of epirubicin therapy
a
P = 0.049.
P = 0.009.
CHF, congestive heart failure; CMF, nine courses of cyclophosphamide (600 mg/m2), methotrexate (40 mg/m2) and 5-fluorouracil (600 mg/m2); LVEF,
left ventricular ejection fraction.
b
pre-treatment LVEF values (P = 0.009) than patients not
developing CHF. The HCD group of patients had 506 measurements of LVEF and the LCD group 98 measurements,
yielding a total of 604 measurements. The overall median
survival after starting chemotherapy before the patients died
of breast cancer was 22 months (range 0.3–84 months) without statistical differences in the HCD and LCD groups, and in
patients with or without CHF.
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 5–6 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
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Figure 1. Median and range left ventricular ejection fraction (LVEF) values before, during and after epirubicin therapy. (A) Patients with high
cumulative dose (HCD) and low cumulative dose (LCD) therapy not developing congestive heart failure (CHF); no, number of patients with
measurement of LVEF. Median and range values are displayed. (B) Ten patients developing CHF after HCD epirubicin. Median and range values are
displayed. Dashed lines indicate lower normal values. ACE, angiotensin-converting enzyme.
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decline in the HCD group was significant after 2–3 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 1B illustrates the impact of epirubicin on cardiac
function in the 10 patients who deteriorated into a clinically
severe, dilated CHF. No patient treated with cumulative doses
below 850 mg/m2 developed CHF in the observation period.
The pre-treatment LVEF values of a median 53% were lower
in this group than the 61% in the patients not developing CHF
(P = 0.009). Median LVEF values during chemotherapy
paralleled values in the group without CHF, but at a lower
level. When presenting with symptomatic signs of CHF, the
patients had an absolute LVEF value of a median 25%
(18–35%).
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 (1.5–60 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.
As seen in Figure 1B, cardiac function continued to deteriorate on digitalo–diuretic therapy for the following median
3 months. Long-acting ACE inhibitor therapy was then started.
Despite a low blood pressure of a median 100/70 mmHg, ACE
inhibitor doses were progressively doubled twice a week from
an initial 1.25–2.5 mg/day to 15 mg/day enalapril or 10 mg/day
ramipril. The therapy was well tolerated. No patients had
first-dose hypotension and blood pressure stabilized at about
100/70 mmHg. As seen in Figure 1B, almost all LVEF values
returned to normal after a median 3 months of ACE inhibitor
therapy, and remained stable in the follow-up period of a
median 33 months (15–60 months). Patients returned to
NYHA class I (n = 7) to II (n = 3). On chest X-rays the lung
fields and the cardiac silhouette normalized, except in one
fatal male case with persistent pronounced dilatation. Light
microscopy of the heart in the patient who died of CHF
showed a considerable fibrous thickening of the endocardium
due to collagenous tissue, and severe interstitial fibrosis with a
remarkable absence of inflammatory cells. The vessels all
appeared normal without inflammation.
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 10–13 LVEF units after 4–5 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 pretaxane era. Extensive second-line therapy with HCDs of 40–
60 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 Kaplan–Meier 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
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Figure 2. Risk of epirubicin-induced congestive heart failure (CHF) and recovery after angiotensin-converting enzyme (ACE) inhibition. (A) Actuarial
risk of developing CHF after 1000 mg/m2 epirubicin (850–1000 mg/m2). Bars indicate patients at risk at latest follow-up or death without CHF.
(B) Probability of recovery with and without ACE inhibition. The probability of recovering 15% in left ventricular ejection fraction (LVEF), after a
relative decline from pre-treatment values of at least 20%. The filled square indicates 18 patients with a relative fall of 20% or more in LVEF without a
subsequent measurement. Bars indicate patients with a relative fall of 20% in LVEF with a subsequent measurement ‘at risk’ for recovery (n = 34). The
open circle indicates the one male patient who died of progressive CHF 10 months after 850 mg/m2 epirubicin despite ACE inhibition.
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Figure 3. Iso-cardiotoxic decline curves for high cumulative dose (HCD) and low cumulative dose (LCD) epirubicin. Solid lines indicate the cumulative
decline distributions for patients treated with HCD epirubicin, dashed line for LCD. Bars indicate patients at risk. Percentages are actuarial calculations
by Kaplan–Meier estimates.
iso-decline curves for a 20% and 25% reduction in cardiac
function. The most susceptible HCD patients showed a 20%
reduction in cardiac function 2–3 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 postanthracycline 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.
Figure 4 illustrates the influence of aging on cardiotoxic
outcome by displaying only the 25% iso-cardiotoxic decline
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curve (dashed line). The HCD group of patients was subdivided by their median age of 50 years at therapy (solid
lines). Patients above 50 years had an actuarial 68% risk of
developing such a severe reduction in cardiac function compared with 36% for patients under 50 years of age (P <0.001),
demonstrating a dramatic increase in cardiotoxic susceptibility
with advancing age. For the patients above 50 years, only 22%
of the cardiotoxic events took place during chemotherapy
while the majority occurred in the post-anthracycline period,
with a median onset after 3–4 months. In both age groups
some late declines occurred after 3–4 years.
Figure 5 displays the 30% and 35% cardiotoxic decline levels
among the 10 patients eventually developing CHF (dashed
line) and the 75 HCD group of patients not developing clinical
symptoms of cardiotoxicity (solid lines). The 10 patients who
eventually developed CHF had a total of 92 measurements of
LVEF, with 32 obtained during chemotherapy and 60 in the
follow-up period. Both groups had a peak onset of cardiotoxic
decline 3–4 months after terminating epirubicin therapy. As
proposed in the guidelines mentioned in the Introduction, a
predefined degree of reduction in cardiac function is often
used for discontinuing further anthracycline therapy. Eight of
the 10 patients who eventually developed CHF underwent a
measurement of LVEF just before 1000 mg/m2 of epirubicin,
but only three of these had a decline of 30%. In the subclinical
group, only three of the 11 patients who eventually had a 30%
Figure 4. Age and cumulative dose-dependent epirubicin cardiotoxicity. The actuarial cumulative 25% iso-cardiotoxic decline curves are indicated for
all patients (dashed lines) and above and below a median age of 50 years (solid lines). HCD, high cumulative dose; LCD, low cumulative dose.
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decline in cardiac function developed this during chemotherapy, while the majority (8 of 11) deteriorated in the postanthracycline period. The figures illustrate the low predictive
value of functional monitoring for developing CHF in close
connection with anthracycline administration.
Discussion
Epirubicin cardiotoxicity was closely coupled to the cumulative dose, with a dramatic increase with advancing age and a
striking variation in individual susceptibility, possibly reflecting inherent differences. Epirubicin induced a threatening,
slowly progressive deterioration of cardiac function with a
displaced onset of 3 months or more after drug administration.
Cardiotoxicity was primarily unmasked in the post-anthra-
cycline period, continuing years after treatment. The more
severe the cardiotoxicity, the longer time for its expression. At
a cumulative dose of 850–1000 mg/m2 epirubicin an actuarial
estimation of 15% of the patients experienced a 25% relative
reduction in LVEF 3 weeks after terminating therapy, increasing to 59% after 3 years. One year after terminating epirubicin
therapy, 11% of the patients deteriorated into a severely dilated
CHF, increasing to 20% after 5 years. Although alarmingly
high these estimates are probably still too low, since the numbers might have been even higher with longer observation time
had the patients not died from breast cancer. Retrospective
observations support the findings of a displaced and retarded
functional effect of anthracyclines. The increased survival
among children and young adults after anthracycline therapy
has shown that long-term cardiotoxicity may appear years to
Figure 5. Prediction of clinical congestive heart failure (CHF) by left ventricular ejection fraction monitoring. In the intention to treat with 1000 mg/m2
epirubicin group of patients, the 10 patients who eventually developed CHF (dashed lines) and the 75 patients with varying degrees of subclinical
cardiotoxicity (solid lines) are separated.
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decades after treatment [3, 11, 17, 18]. An alarming fraction of
more than 65% of survivors of leukemia in childhood has
shown progressive cardiac abnormalities 6 years after completing anthracycline therapy [3, 15, 17].
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 10–14 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 postanthracycline 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 [21–28]. 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 agedependent 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, 23–26, 37–39]. 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, 7–10]. 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 III–IV) 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
709
prevention of cardiotoxicity in the post-anthracycline period
by ACE inhibition.
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