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European Journal of Heart Failure 2007 9(4):409-414; doi:10.1016/j.ejheart.2006.09.007
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© 2007 European Society of Cardiology

Monitoring left ventricular function in adults receiving anthracycline-containing chemotherapy

Mark Belhama,*, Anton Krugerb, Sophie Mephamb, Giorgio Faganelloa and Colin Pritchardc

a Department of Cardiology, Royal Cornwall Hospital Truro, Cornwall, United Kingdom
b Department of Haematology, Royal Cornwall Hospital United Kingdom
c Peninsula Research and Development Support Unit, Royal Cornwall Hospital United Kingdom

* Corresponding author. Tel.: +44 1872 253599 (Business), +44 1872 241689 (Home). E-mail address: markbelham{at}zoom.co.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 7. Future directions
 References
 
Aims: To assess prospectively (1) the incidence of early anthracycline-induced cardiotoxicity; (2) the best predictor for identifying individuals at risk of developing functional cardiotoxicity; and (3) the most sensitive standard echocardiographic measure for the detection of anthracycline-induced changes in left ventricular (LV) function.

Methods: Sixty-seven consecutive patients (45 male, mean age 50±18 years) requiring doxorubicin-containing chemotherapy were enrolled. Clinical and echocardiographic assessments occurred before they received any anthracycline, after low-dose anthracyclines and 1–3 months after completion of their chemotherapy.

Results: Twenty six percent of patients without significant pre-existing cardiac disease developed cardiotoxicity. The parameter that best predicted the development of functional cardiotoxicity was the change in EF between baseline and low dose with an area under the curve of 0.92. The Tei index detected declines in LV function earlier in the course of treatment with anthracyclines and to a greater significance than any other standard echocardiographic measurement but did not predict functional cardiotoxicity.

Conclusions: All patients receiving potential cardiotoxic chemotherapy should be under the care of a cardiologist and have their EF monitored closely.

Key Words: Anthracyclines • Chemotherapy • Cardiotoxicity • Left ventricular function • Tei index • Ejection fraction

Received March 10, 2006; Revised July 31, 2006; Accepted September 14, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 7. Future directions
 References
 
Anthracycline antibiotics are effective chemotherapeutic agents used in the treatment of haematological malignancies and solid tumours [1,2]. A major limitation to the use of anthracyclines is their potential for causing adverse cardiac effects that can necessitate the interruption or alteration of chemotherapy treatment. These adverse effects include cardiac arrhythmias, myo-pericarditis and myocardial infarction which are rare, idiosyncratic and usually occur during the course of chemotherapy [3]. More commonly, however, cardiotoxicity results in declines in left ventricular function mediated by myocardial apoptosis [4] which can culminate in development of heart failure during or at almost any time after the end of the course of chemotherapy [5,6]. The main aim of this study was to assess prospectively the incidence of all forms of early (within 3 months of completion of chemotherapy) cardiotoxicity with current anthracycline-containing chemotherapy regimes and identify the best predictor for identifying individuals at risk of developing functional cardiotoxicity. The secondary aim was to identify the most sensitive standard echocardiographic measure for the detection of anthracycline-induced changes in left ventricular (LV) function.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 7. Future directions
 References
 
2.1. Study population
Sixty-seven consecutive patients (45 male, 22 female) aged 16-88 years old (mean 50±18 years) requiring doxorubicin-containing chemotherapeutic regimes for haematological malignancies or solid tumours were enrolled. The study was designed such that each individual would be assessed clinically and echocardiographically before they received any anthracycline, after low-dose anthracyclines and 1-3 months after completion of their chemotherapy. All patients gave written informed consent prior to participating in the study. The local research and ethics committee approved the study.

2.2. Echocardiography
Patients underwent comprehensive two-dimensional and Doppler echocardiographic examinations performed by a single experienced operator using a Vivid 7 machine (General Electric, Horton, Norway) in accordance with recognised standards [7,8]. The ejection fraction (EF) was calculated using the modified Simpson's rule with a value of 50% or more being considered as normal [9]. In addition to traditional parameters of left ventricular systolic and diastolic function, the Tei index was calculated and Doppler tissue imaging (Dti) derived longitudinal systolic (Sa) and early diastolic (Ea) velocities were measured. The Tei index was calculated as the sum of the isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT) divided by the ejection time (ET) as previously described [10]. The longitudinal Sa and Ea velocities were obtained on-line using spectral Dti in the apical 4 chamber view placing a 5 mm pulsed wave sample volume at the level of the lateral mitral annulus [11]. Respiratory manoeuvres (e.g., end expiratory apnoea) were used where possible to enhance data quality; if used at baseline the manoeuvres were repeated on subsequent studies to maintain consistency. Each parameter was measured from 3 to 5 consecutive beats and averaged [12].

2.3. Classification of functional cardiotoxicity
Classification of functional cardiotoxicity at our institute is a modification of that which has been described by Schwartz et al. [13] and is based on clinical and echocardiographic criteria. Functional cardiotoxicity is defined as mild (a decrease in EF>10% from baseline with a final value >50%), moderate (a decrease in EF>10% from baseline with a final value <50% and no symptoms or signs of heart failure) and severe (a decrease in EF>10% from baseline with a final value <50% and symptoms or signs of heart failure or a decrease in EF of any % leading to a final value <40% irrespective of symptoms or signs of heart failure).

2.4. Statistics
A single examiner made all the measurements; the intra-observer variability for each parameter was evaluated by calculating the coefficient of reproducibility using the method of Bland and Altman [14] (Table 1).


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  		Table 1 Intra-observer variability

 
To identify the best predictor for identifying patients who would develop functional cardiotoxicity the outcome measure used was the presence of a 10% decline in ejection fraction between baseline and completion. Associations between this decline in ejection fraction and baseline characteristics or changes in measures of cardiac function between baseline and low dose were analysed using the binary logistic regression procedure in SPSS 14. Parameter estimates were reported as odds ratios together with their 95% confidence intervals. The odds ratios provide an estimate of the change in the odds of a 10% decline in ejection fraction associated with a unit increase in the predictor variable. The sensitivity and specificity were illustrated by a standard receiver operator curve (ROC) and assessed in terms of the area under the curve.

To compare echocardiographic measures and identify the parameter that demonstrated the earliest and most significant change, data were expressed as mean±one standard deviation (S.D.). The data were normally distributed so comparison of each measurement pre-chemotherapy versus low dose/completion of anthracycline-containing chemotherapy and low dose versus completion of anthracycline-containing chemotherapy was accomplished with paired Student's t-tests. A p-value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 6. Limitations
 7. Future directions
 References
 
The outcomes of the 67 patients enrolled are depicted in a flowchart (Fig. 1). One patient withdrew from the study. Five patients had pre-existing cardiac disease; two with cardiomyopathy and three with atrial fibrillation (AF). In all except one patient (with AF) the finding of significant cardiac pathology was new and not predicted by the responsible physician. One patient with AF did not receive anthracycline-containing chemotherapy. The other two patients with AF received anthracycline-containing chemotherapy; one died of non-cardiac causes and the other completed the chemotherapy regime without complication or significant decline in left ventricular function. One patient with pre-existing cardiomyopathy is still awaiting a decision regarding chemotherapy regime; the other patient (baseline ejection fraction 35%) required anthracycline-containing chemotherapy for overriding haematological indications. She was pre-treated with an angiotensin-converting enzyme inhibitor and given dexrazoxane in conjunction with her chemotherapy treatment. She received a total of 300 mg/m2 of doxorubicin without a decline in ejection fraction but died later from non-cardiac causes.


Figure 01
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  		Fig. 1 Outcomes flowchart.

 
The remaining 61 patients consisted of 53 males and 18 females, aged 50 (±18) years, who received an average of 93±33 mg/m2 doxorubicin at time of low-dose study and 293±103 mg/m2 doxorubicin at time of completion study. Prior to commencing treatment, there were 2 patients with ischaemic heart disease and 6 with hypertension (1 with co-existing diabetes mellitus). There were no other patients with relevant past medical history (PMH) within the study population. Baseline echocardiography revealed that all patients had normal left ventricular systolic function (i.e., an EF of 50% or more). Fifteen patients had pre-treatment age-adjusted left ventricular diastolic dysfunction as defined by the work of Mottram et al. [15] (all mild [grade I]).

Seven patients died of non-cardiac causes prior to completion of their chemotherapy treatment. There were no cardiac deaths.

Two patients developed sustained but asymptomatic atrial fibrillation (AF). The first was a female aged 66 years and the second a male of 59 years; neither had any significant PMH and both had normal pre-treatment left ventricular systolic and diastolic function. They developed the arrhythmia after 50 mg/m2 and 300 mg/m2 of doxorubicin (CHOP regime), respectively, without any clinically relevant change in functional parameters. Prior to diagnosing the female patients' AF she had suffered an episode of neutropenic sepsis with electrolyte disturbances (lowest serum values of potassium, magnesium and corrected calcium 3.2, 0.68 and 1.96 mmol/L, respectively) that may have been the precipitant; she subsequently reverted back to sinus rhythm without specific intervention. The male patient had a short paroxysm of AF after an episode of neutropenic sepsis (without electrolyte disturbance) early in his treatment course before developing persistent AF without identifiable precipitant; he was listed for elective cardioversion but died of non-cardiac causes before this was undertaken.

One patient (male aged 50 years) with no cardiac risk factors suffered a myocardial infarction (MI) 12 days after receiving his fourth (uncomplicated) course of CHOP (total of 200 mg/m2). He underwent coronary angiography; there was a discrete lesion in his left anterior descending artery that was stented. Despite the MI, the left ventricular systolic function remained normal.

Two patients developed severe functional cardiotoxicity (declines in left ventricular ejection fraction to less than 40%) with associated heart failure and required treatment with vasodilators and beta-blockers. Both were males (aged 75 and 84 years) without significant past medical history but with evidence of pre-treatment age-adjusted diastolic dysfunction. The decline in LVEF occurred after 200 mg/m2 and 150 mg/m2 of doxorubicin (CHOP regime), respectively.

There were a further two patients that developed moderate functional cardiotoxicity (one male aged 59 years with no PMH but with pre-treatment diastolic dysfunction who received a total of 400 mg/m2 and one male aged 49 years with no PMH and normal pre-treatment LV function who received a total of 200 mg/m2). Nine patients developed mild functional cardiotoxicity (6 male aged 49±17 years receiving an average total of 300±83 mg/m2. Two patients had pre-treatment diastolic dysfunction [1 with IHD].)

The parameter that best predicted the development of functional cardiotoxicity was the change in EF between baseline and low dose with an area under the curve of 0.92 (Fig. 2). A change of 4% had a sensitivity of 91% and a specificity of 83% for the detection of a 10% or greater fall in EF from baseline with a negative predictive value of 96% and a positive predictive value of 67%. A change of 5% had a sensitivity of 73% and a specificity of 86% for the detection of a 10% or greater fall in EF from baseline with a negative predictive value of 89% and a positive predictive value of 67%.


Figure 02
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  		Fig. 2 ROC Curve: Change in EF from baseline to low dose.

 
The results of the comparisons between echocardiographic measures are detailed in Table 2. The earliest change of significance was an increase in the Tei index that occurred after low dose. It should be noted, however, that although statistically significant the degree of change is less than the coefficient of reproducibility. After completion, there was a significant increase in the Tei index and decline in the ejection fraction, fractional shortening (FS) and longitudinal systolic contraction (Sa); all degrees of change except the Sa were greater than the respective coefficient of reproducibility. The changes in Tei index were of greatest statistical significance.


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  		Table 2 Comparing left ventricular function pre-treatment to left ventricular function after low dose/completion of anthracycline-containing chemotherapy

 
There was no significant change in global or longitudinal diastolic parameters (E/A, Ea or E/Ea) after low dose or completion when compared to pre-treatment values.

Comparing the left ventricular function after low dose to the left ventricular function after completion of chemotherapy there was a significant change in EF and FS but these changes were less than the respective coefficient of reproducibility.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 6. Limitations
 7. Future directions
 References
 
Prior to commencing chemotherapy four patients were found to have serious, previously unrecognised, cardiac disease. A further 16 patients (26%) had a cardiac complication during the period of follow-up. These findings underline the importance of pre- and peri-treatment cardiological assessment and monitoring of these individuals. As the average age of the population treated with anthracyclines is likely to increase, the argument for cardiological involvement will only increase further.

To compare our findings with those of other studies, only those that we classified as having moderate or severe functional cardiotoxicity should be considered as this equates more readily to traditional outcome measures. Eight percent (4/51) of survivors developed moderate or severe functional cardiotoxicity in our study; this is a similar event rate to that identified in other prospective studies [16-18] but significantly higher than the 1-2% event rate quoted in some retrospective studies [19,20]. These differences are likely to be due to what data are collected and the way they are collected, with retrospective studies underestimating the true incidence. In addition, the average age of the study population may be an important factor, with studies including a high proportion of young people [19,20] having a lower incidence of early cardiac events.

With respect to predicting cardiotoxicity, the value of early declines in EF has been described by Nousiainen et al. [17] using radionuclide ventriculography. They investigated a smaller population of similar age who received a higher cumulative anthracycline dose and demonstrated ROC characteristics similar to this study with an area under the curve of 0.858. In the study by Nousiainen et al. [17] a change in EF of 4% between pre-treatment and low-dose chemotherapy had a sensitivity of 90% and a specificity of 72% for the detection of a 10% or greater fall in EF from baseline with a negative predictive value of 93% and a positive predictive value of 64%. The change in EF between pre-treatment and low dose is, therefore, a powerful predictor of outcome irrespective of which method is used to measure it. In addition, the results presented in this study combined with those of Nousiainen et al. [17] and Schwartz et al. [13] suggest that declines in EF are stepwise and potentially predictable within individuals.

Changes in EF can clearly predict the development of early functional cardiotoxicity but the parameter itself changes later in the treatment course and to a less significant degree than the Tei index in patients receiving anthracyclines. This relative insensitivity of the ejection fraction has previously been described [21-23] and probably relates to the fact that it is a measure of only one part of left ventricular function (i.e., systolic function). The Tei index on the other hand is a measure of global (systolic and diastolic) function without geometrical assumptions; it correlates well with invasive measurements [24] and has been validated in the assessment of ventricular function with higher values conferring poorer prognosis [25-29]. Specifically relating to anthracyclines, the Tei index has identified significant deteriorations in cardiac function after administration of low doses in the paediatric population [30-33]. Our study has demonstrated the ability of the Tei index to detect anthracycline-induced deteriorations in left ventricular function in the adult population earlier in their course of treatment and with more statistical significance than the ejection fraction or any other routinely measured echocardiographic parameter. Despite this apparent sensitivity, the Tei index failed to predict the development of functional cardiotoxicity. Previous investigators have also noticed a lack of concordance between time interval measurements and ejection fraction [34] and although longer term follow-up may identify that the Tei index can offer predictive value for overall cardiac risk in patients receiving anthracycline-containing chemotherapy regimes, there is no evidence to support this at present.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
6. Limitations
 7. Future directions
 References
 
Treatment with anthracycline-containing chemotherapy regimes is associated with a high degree of cardiotoxicity both clinically and sub-clinically. The development of functional cardiotoxicity can be predicted by changes in ejection fraction between echocardiographic studies performed pre-treatment and after low-dose anthracyclines. These points combined suggest that all patients receiving potential cardiotoxic chemotherapy should be under the care of a cardiologist and have their EF monitored closely.


   6. Limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
7. Future directions
 References
 
This study compared echocardiographic parameters that can be readily measured in the majority of echo labs. All conceivable echocardiographic measurements were not, therefore, assessed. The use of parameters such as strain and strain rate may further improve the ability of echocardiography to detect early anthracycline cardiotoxicity and prospective evaluation of these parameters is warranted.

Changes in echocardiographic parameters were not compared with changes in natriuretic peptides. Further investigation to compare changes in natriuretic peptides to changes in each echocardiographic parameter is ongoing at our institute but it should be noted that previous studies have shown that increased secretion of natriuretic peptides during doxorubicin treatment is a compensatory phenomenon that occurs after observed decreases in ejection fraction [35].


   7. Future directions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 7. Future directions
References
 
With timely intervention, it would be possible to decrease morbidity and mortality in individuals who develop heart failure having survived malignancy. Our group is committed to finding early and accurate predictors of cardiotoxicity and invite collaboration from other investigators.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 7. Future directions
 References
 

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