Departments of 1 Pharmacy, 2 Hematology, 3 Cardiology and 4 Nuclear Medicine, Besançon University Hospital, Besançon, France
Received 23 April 2002; revised 12 August 2002; accepted 16 September 2002
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Abstract |
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To determine the incidence of early cardiotoxicity induced by the CHOP regimen in patients with aggressive non-Hodgkins lymphoma (NHL) and to identify associated risk factors.
Patients and methods:
A retrospective analysis included 135 consecutive patients who had been treated with the CHOP (cyclophosphamide, doxorubicin, vincristin, prednisone) regimen as first-line therapy between 1994 and 2000. The cardiac evaluation was based on a determination of the resting left ventricular ejection function (LVEF) by gated blood-pool imaging. Cardiotoxicity was defined as a significant decrease in LVEF or clinical evidence of congestive heart failure (CHF).
Results:
Twenty-seven (20%) patients developed a cardiac event within 1 year of treatment. Among these, 14 patients had clinical signs of CHF. Three patients died suddenly from presumed cardiac causes. In multivariate analysis, a cumulative dose of doxorubicin >200 mg/m2 [odds ratio (OR) = 4.2, P = 0.005)] and age over 50 years (OR = 2.9, P = 0.03) appeared to be significant risk factors.
Conclusion:
Early clinical and subclinical cardiotoxicity was frequent in patients receiving the CHOP regimen. The threshold of the cumulative dose of doxorubicin appeared to be low: at doses >200 mg/m2, 27% of patients had cardiac events. Elderly patients appeared to be at higher risk. The development of cardioprotective strategies or alternative treatments are mandatory for aggressive NHL patients.
Key words: cardioprotection, cardiotoxicity, congestive heart failure, doxorubicin, non-Hodgkins lymphoma
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Introduction |
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The majority of available data have been reported in childhood and breast cancers. The definition of cardiotoxicity varied in these studies [4]. Early (within 1 year of treatment) and late onset (>1 year after treatment) cardiac abnormalities are commonly distinguished and toxic effects have been defined as clinical or subclinical heart failure [2, 4]. The cumulative incidence of CHF varied from 1.6% to 2.8% [1, 6, 8]. Using more sensitive investigations, Lipschutz et al. [9] showed that 57% of long-term survivors had cardiac abnormalities. In other studies, the incidence of left ventricular ejection (LVE) dysfunction varied from 21% to 31% [1013].
The CHOP (cyclophosphamide, doxorubicin, vincristin, prednisone) regimen is still considered the gold standard in first-line therapy [14]. Surprisingly, there are few data concerning the cardiac consequences of the systematic use of doxorubicin for patients with aggressive non-Hodgkins lymphoma (NHL). Only one study has shown that cardiac toxicity was the predominant late chemotherapy-related effect in long-term survival [15]. The potential cardiotoxicity of first-line therapy should be considered, in relation to the incidence and the long-term prognosis of aggressive NHL patients.
A retrospective study was carried out to analyse the early doxorubicin-induced cardiotoxicity in aggressive NHL patients. The primary objective was to determine the incidence of cardiac abnormalities within 1 year of treatment using the CHOP regimen. The secondary objective was the identification of the risk factors of cardiotoxicity.
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Patients and methods |
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Patients who showed evidence of any cardiac abnormality before the start of chemotherapy were excluded from the study.
All patients were informed of the potential toxicity of chemotherapy, including cardiotoxicity, at the onset of treatment. The current modalities of the cardiac function evaluation were presented. In the case of inclusion in a clinical trial, written informed consent was obtained from all patients, and studies were designed and conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committees.
Early cardiotoxicity
The study was limited to the first year of follow-up, including the period of treatment [2]. According to local practice, cardiac evaluation included baseline physical examination, ECG and determination of the resting left ventricular ejection function (LVEF) by gated blood-pool (GBP) imaging (nuclear scan) [16, 17]. Gated blood-pool imaging was routinely performed before treatment, after four cycles and at the end of first-line chemotherapy (maximum of eight cycles) and/or in the case of clinical abnormalities. All examinations were performed in the same institution. The institutions lower limit of normal value of LVEF was 53%. Cardiac events were defined as either a decline in resting LVEF of 15% from baseline, or a decline in LVEF of <50%, or clinical evidence of CHF.
In patients receiving other treatments [salvage therapy and/or high-dose chemotherapy (HDC)] within 1 year, only cardiotoxicity detected during or at the end of CHOP therapy was considered. All potentially positive (subclinical or clinical toxicity) cases were reviewed by an independent and experienced cardiologist.
Risk factors
The cumulative dose of doxorubicin per square metre of body surface area was calculated for each patient. If the administration of doxorubicin was continued despite the occurrence of cardiac abnormality during the treatment, the cumulative dose at the time of the cardiac event was used in the assessment.
The effects of other factors such as sex, age and pre-existing cardiac risk factors (hypertension, diabetes and hypercholesterolemia) were evaluated [2, 3].
Statistical analysis
Univariate analyses were carried out using the chi-square or Fishers exact tests. At the outset, the cumulative dose of doxorubicin as well as the patients age were broken down into three and six groups (per 100 mg/m2 and 10 years), respectively. Then according to cut-off points, the number of groups could be reduced. Other parameters were considered as dichotomic qualitative variables. All variables with P <0.15 associated by univariate analysis were entered in a stepwise regression model. Interactions between candidate variables were tested.
All analyses were performed using BMDP for Windows (release 7.0, BMDP Inc., Los Angeles, USA). Significance levels were set at 0.05.
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Results |
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In six cases, chemotherapy by the CHOP regimen was interrupted because of cardiac toxicity. In five additional patients with a decreasing LVEF, a cardioprotective treatment by dexrazoxane was administered and additive cycles of chemotherapy could be given.
Risk factors
Among the patients who received involved field radiotherapy following CHOP chemotherapy at the standard dose of 40 Gy (20 fractions), only one was administered on the mediastinum (Table 2).
In a previous analysis, thresholds of toxicity were clearly identified for a cumulative dose of doxorubicin and age (Table 4). Univariate analysis showed that a cumulative dose of doxorubicin >200 mg/m2 and age >50 years were significant factors for early cardiotoxicity. No effect of sex and pre-existing cardiac risk factors was found.
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Discussion |
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In several studies, toxicity has been defined as CHF [1, 6, 8]. The use of more sensitive investigations has led to a wider definition of cardiotoxicity, including subclinical cardiomyopathy [2, 3]. As LVE dysfunction could be asymptomatic, the real clinical impact could be considered to be overestimated. However, it has been shown that a decline in LVEF values was predictive of late clinical manifestations [16, 17]. Furthermore, GBP imaging or echocardiography are relatively insensitive when used to detect early myocardial damage [2]. The evaluation of diastolic function would probably be more sensitive [19]. The potential interest of cardiac serum troponin-T levels has been suggested, but this parameter has not yet been validated [20].
Our analysis showed that 20% of NHL patients treated by the CHOP regimen developed cardiac abnormalities within 1 year of treatment. In adult patients, available data are restricted to metastatic breast cancer patients. Early cardiotoxicity has been estimated as between 21% and 31%, but many women had received prior chemotherapy and/or radiotherapy [12, 13]. Among the 27 cases of cardiotoxicity which are reported in our study, 14 (52%) had clinical symptoms of CHF within 1 year of treatment. These results are in agreement with those of two recent population-based studies [21, 22], which showed that among the patients who had LVE dysfunction, 50% had clinical symptoms of CHF.
In our study, three (21%) of the symptomatic patients died from a cardiac event within 1 year. In Von Hoff et al.s study [1], the mortality attributed to anthracycline-induced CHF was estimated as 40%. In more recent studies, this rate has varied from 8% to 23% [5, 6, 8]. All these reports, including our study, were based on retrospective data, and mortality related to doxorubicin cardiotoxicity could have been influenced by other confounding factors. However, 1230 cases of cardiomyopathy were recently analysed, with an overall mortality rate of 34% [7]. The doxorubicin-related form appeared to have especially poor long- term prognosis compared to idiopathic cardiomyopathies (relative risk = 3.4, P <0.001).
The cumulative dose of doxorubicin is the major factor of cardiotoxicity [1, 5]. An empirical threshold of 500 mg/m2 is commonly used and the risk appeared to be limited below 300 mg/m2 [3, 6, 13, 23]. With the CHOP regimen, our study identified a lower threshold for cumulative doses. Over 200 mg/m2, 27% of patients had subclinical or clinical cardiomyopathy. If these results are confirmed, the hypothesis can be made that the cardiotoxicity of doxorubicin could be increased by the presence of associated drugs. Cyclophosphamide is commonly associated with doxorubicin in childhood and breast cancers. Lipschultz et al. [5] suggested that cardiac effects could be increased by high doses of corticosteroids. Additionally, the potential role of vincristin should be investigated.
Another finding of our study was that patients over 50 years of age had a significantly increased risk of cardiotoxicity. The specific effect of age has been demonstrated in children, but the results cannot be transposed to adults [1, 5, 9]. CHOP is now considered to be the standard regimen in all patients with aggressive NHL, including elderly patients [24, 25]. Using the equation of the logistic regression model, the probability of developing a cardiac event in patients over 50 years of age and receiving more than 200 mg/m2 of doxorubicin could be estimated at 33% within 1 year of treatment. These patients should be considered as a high-risk population.
A limiting factor of our study was the short follow-up period. Several studies have reported late clinical and subclinical cardiomyopathy occurring in previously asymptomatic children [6, 911]. In NHL patients, late LVE dysfunction has been identified in 14% of long-term survivors, but the study included both children and adults and the chemotherapy regimens varied [15]. Nevertheless, early identification of a population at risk is important for the short-term management and the long-term follow-up of patients receiving doxorubicin. Furthermore, in two recent studies [6, 8], 76% and 89%, respectively, of all cases of CHF have been reported within 1 year of treatment.
As early cardiotoxicity would appear to be a severe problem in aggressive NHL patients, preventive strategies need to be considered. In adults, it has been suggested that a prolonged infusion over 48 or 96 h may be less toxic than a short infusion [18]. However, this finding has not been confirmed and doubt concerning the preservation of antitumoral activity remains [2]. The use of epirubicin in aggressive NHL has not been conclusive and its advantage over doxorubicin on an equimolar basis is unclear [3, 26]. Although randomised trials have shown that dexrazoxane provides an effective cardioprotection in breast cancer, their design has been questioned and the role of this agent remains unclear [12, 27]. There are no available data for NHL patients and the recent guidelines of the American Society of Clinical Oncology are highly cautious concerning the use of dexrazoxane for tumours other than breast cancer [23]. The use of liposome-encapsulated doxorubicin could be considered to be a more promising approach [13].
Despite the usual limitations of retrospective analyses, our pragmatic study showed that early cardiac abnormalities and symptomatic forms are frequent in patients receiving the CHOP regimen. In addition, hematopoietic stem cell transplantation plays a major and increasing role in the treatment of these patients [28, 29]. The cardiotoxicity of HDC is probably dependent on regimen, but a history of declining LVEF values would appear to be a predictive factor for cardiac toxicity in NHL patients undergoing HDC [30]. At this point in time, the role of anthracyclines in first-line therapy remains unquestionable. Thus, the development of cardioprotective strategies or alternative treatments are mandatory for aggressive NHL patients.
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Footnotes |
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References |
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