Acute decompensated heart failure as a reason of premature chemotherapy discontinuation may be independent of a lifetime doxorubicin dose in lymphoma patients with cardiovascular disorders Sebastian Szmit, Wojciech Jurczak, Jan Maciej Zaucha, Monika DługoszDanecka, Barbara Sosnowska-Pasiarska, Ewa Chmielowska, Monika Joks, Joanna Drozd-Sokołowska, Wanda Knopi´nska-Posłuszny, Wojciech Spychałowicz, Beata Kumiega, Grzegorz Charli´nski, Marta Morawska, Grzegorz Słomian PII: DOI: Reference:
S0167-5273(17)31101-4 doi:10.1016/j.ijcard.2017.02.073 IJCA 24599
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
14 July 2016 6 February 2017 20 February 2017
Please cite this article as: Szmit Sebastian, Jurczak Wojciech, Zaucha Jan Maciej, Dlugosz-Danecka Monika, Sosnowska-Pasiarska Barbara, Chmielowska Ewa, Joks Monika, Drozd-Sokolowska Joanna, Knopi´ nska-Posluszny Wanda, Spychalowicz Wojciech, Kumiega Beata, Charli´ nski Grzegorz, Morawska Marta, Slomian Grzegorz, Acute decompensated heart failure as a reason of premature chemotherapy discontinuation may be independent of a lifetime doxorubicin dose in lymphoma patients with cardiovascular disorders, International Journal of Cardiology (2017), doi:10.1016/j.ijcard.2017.02.073
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ACCEPTED MANUSCRIPT Acute decompensated heart failure as a reason of premature chemotherapy discontinuation may be
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independent of a lifetime doxorubicin dose in lymphoma patients with cardiovascular disorders.
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Sebastian Szmit (1), Wojciech Jurczak (2), Jan Maciej Zaucha (3), Monika Długosz-Danecka (2), Barbara SosnowskaPasiarska (4), Ewa Chmielowska (5), Monika Joks (6), Joanna Drozd-Sokołowska (7), Wanda Knopińska-Posłuszny (8),
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Wojciech Spychałowicz (9), Beata Kumiega (10), Grzegorz Charliński (7), Marta Morawska (11), Grzegorz Słomian (12)
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(1) Department of Pulmonary Circulation and Thromboembolic Diseases, Centre of Postgraduate Medical Education, Otwock, Poland
(2) Department of Hematology, Jagiellonian University, Kraków, Poland.
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(3) Department of Propedeutic Oncology, Medical University of Gdansk & Gdynia Oncology Center, Gdynia, Poland.
(4) Department of Oncocardiology, Holycross Cancer Center, Kielce, Poland
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(5) Nicolaus Copernicus University in Toruń & Clinical Oncology Department of Oncology Center in Bydgoszcz, Poland
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(6) Department of Hematology and Bone Marrow Transplantation, Poznań University of Medical Sciences, Poznań, Poland.
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(7) Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
(8) Hematology Department, Independent Public Health Care Ministry of the Interior of Warmia and Mazury Oncology Center & University of Warmia and Mazury, Olsztyn, Poland
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(9) Internal Medicine and Oncology Clinic, Silesian Medical University, Katowice, Poland.
(10) Departament of Hematooncology, Markiewicz Memorial Oncology Center, Brzozów, Poland
(11) Hematooncology and Bone Marrow Transplantation Clinic & St. John's Cancer Center, Lublin, Poland
(12) Department of Clinical Oncology, Regional Specialized Hospital No. 3, Rybnik, Poland
Corresponding author: Sebastian Szmit, Department of Pulmonary Circulation and Thromboembolic Diseases, Centre of Postgraduate Medical Education, European Health Centre Otwock, Borowa 14/18, 05-400 Otwock, Poland, fax: +48 22 7103169, ph: +48 22 710 30 52, e-mail:
[email protected]
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ACCEPTED MANUSCRIPT ABSTRACT Background. Algorithm of anthracycline-based chemotherapy with favourable cardio-oncological outcome should be clearly re-defined for lymphoma patients with significant pre-existing cardiovascular diseases. A
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clinical benefit of liposomal forms of anthracycline is still debatable.
Methods. Polish registry included observations of 138 lymphoma patients with concomitant cardiovascular
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disorders who received liposomal doxorubicin as cardioprotective alternative of conventional form. It was created to analyse the importance of a strategy of administration of conventional/liposomal doxorubicin and a lifetime doxorubicin dose for development of acute decompensated heart failure (ADHF) as a reason of
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premature chemotherapy discontinuation.
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Results. ADHF was the cause of premature termination of chemotherapy only in 11 patients (7.97%). The five new episodes of ADHF related to liposomal doxorubicin were recorded in subgroup of 70 patients with preexisting heart failure (7.14%). There was the similar incidence of ADHF when liposomal doxorubicin was
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applied after conventional form in dose 200mg/m2 or if earlier signs of iatrogenic myocardial damage was
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recognised: 5 cases in subgroup of 51 patients with baseline cardiovascular risk factors (9.8%). ADHF was observed in one of 17 patients (5.88%) receiving liposomal doxorubicin as second line chemotherapy after first
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line with conventional doxorubicin. Consequently throughout the study group ADHF didn't depend on the total cumulative dose of all types of doxorubicin: OR=0.85; 95%CI: 0.66-1.10; p=0.22 for each 50mg/m2.
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Conclusion. The schedule of administration of conventional/liposomal doxorubicin can decide that lifetime combined doses of anthracyclines become insignificant for ADHF occurrence and premature discontinuation of chemotherapy in lymphoma patients with pre-existing cardiovascular disturbances.
Key words: lymphoma; chemotherapy; anthracyclines; liposomal doxorubicin; acute decompensated heart failure; cardio-oncology;
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ACCEPTED MANUSCRIPT 1. INTRODUCTION Anthracycline-based chemotherapy regimens are a standard of care in the first line treatment of Diffuse Large B cell Lymphoma (DLBCL). Their potent antitumor activity is associated with an increased incidence of
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cardiotoxicity [1]. Clinical observation shows that particularly in patients with the history of cardiovascular disorders including cardiac arrhythmias, anthracycline therapy may result in premature cardiovascular mortality
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[2].
Mechanisms of anthracycline cardiotoxicity has been a subject of many analyses and discussions.
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Occurrence of clinical manifestation, whether in the form of asymptomatic cardiac dysfunction or a full symptomatic heart failure, depends from individual genetic predisposition and existence of concomitant clinical
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risk factors [3,4], especially arterial hypertension and ischaemic heart disease [5,6]. Each successive anthracycline dose may result in cardiomyocytes damage, thus some historical
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observations reported that there is a direct relationship between the anthracycline dose and the likelihood of heart
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failure development [7]. New available data confirm that cardiac prognosis of patients treated with anthracycline-based regimens depends on the cumulative dose of conventional doxorubicin and the value of
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left ventricular ejection fraction (LVEF) assessed after the end of the chemotherapy [8]. The real prognosis of lymphoma patients with significant pre-existing
cardiovascular disorders receiving antracycline-based
chemotherapy is still unknown. Even a clinical benefit of liposomal forms of anthracycline, newer and
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theoretical safer but more expensive drugs, is still debatable [9,10,11]. The main purpose of the study was to assess the importance of a strategy of administration of conventional/liposomal doxorubicin and a lifetime cumulative dose of doxorubicin for development of acute decompensated heart failure (ADHF) in lymphoma patients with concomitant cardiovascular disorders. ADHF was understood as clinically significant cardiotoxicity and ipso facto one of the main reasons of premature discontinuation of anthracycline-based chemotherapy. 2. MATERIAL AND METHODS 2.1 The details of the registry The study was initiated and conducted by the Polish Lymphoma Research Group (PLRG) and the East European Branch of International CardiOncology Society. The main intention of the study was to perform a
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ACCEPTED MANUSCRIPT prospective registry of real world outcomes of all new consecutive lymphoma patients with serious pre-existing cardiovascular disorders who required chemotherapy with anthracyclines and received liposomal doxorubicin as cardioprotective alternative of conventional form. Lymphoma patients without baseline cardiovascular disorders
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were not recorded. The study was the nature of the registry of daily practice in Poland, all patients' clinical data were
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collected in accordance with the guidelines of the local bioethics committees. The selected eleven Polish oncological centres belonging to PLRG and one cardiac department as the independent supervisor were active in
included.
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2.2. The definitions of the treatment subgroups
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this registry. Finally the observations of 138 patients treated in the period from January 2014 to June 2016 were
Modification of standard anthracycline-based therapy and replacing conventional doxorubicin by nonpegylated liposomal form was in accordance with the Polish guidelines for cardio-oncology [12].There were
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three clinical situations for a cardioprotective usage of liposomal doxorubicin instead of conventional form. They
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reflect our policy to start therapy with conventional doxorubicin wherever possible – for efficacy, and continue
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the treatment with liposomal form to deliver the required dose with reduced cardiac toxicity. Subgroup A. Patients with baseline contraindications for conventional doxorubicin i.e. recognised earlier heart failure with reduced or preserved left ventricular ejection fraction (LVEF) as a consequence of
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coronary artery disease, arterial hypertension, valvular disease or arrhythmias who might be treated upfront with liposomal doxorubicin (n=70). Heart failure was recognized in accordance with obligatory guidelines of European Society of Cardiology (ESC) [13]. Symptoms of exercise intolerance might be at most in I or II class according to NYHA. Subgroup B. Patients without baseline absolute contraindications for conventional doxorubicin i.e. without diagnosis of heart failure or significant asymptomatic cardiac dysfunction but with classic cardiovascular risk factors like coronary artery disease, arterial hypertension, obesity, diabetes mellitus etc. They received sequential treatment with conventional followed by liposomal doxorubicin (n=51). There was the clear indication for a possible switch from conventional to liposomal doxorubicin: after administration 200 mg/m2 of conventional doxorubicin or at lower dose if left ventricular impairment on echocardiography analysis or each other clinical sign of early cardiac damage were observed. This algorithm met the criteria for the use of
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ACCEPTED MANUSCRIPT liposomal doxorubicin proposed by the latest ESC Position Paper on cancer treatments and cardiovascular toxicity [14]. Subgroup C. Patients without cardiac systolic dysfunction who received previously over 200 mg/m2 of
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conventional doxorubicin and were qualified for second line chemotherapy with liposomal doxorubicin as the
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best option of anticancer therapy (n=17). 2.3. Evaluation of cardiac status
At baseline all patients were thoroughly evaluated by a cardiologist who evaluated cardiac status by
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echocardiographic examinations and assessment of history of previous cardiac events and exercise tolerance. In all cases treatment of pre-existing, concomitant cardiovascular diseases had to be optimal and consistent with the
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current recommendations of the European Society of Cardiology applicable to heart failure, coronary artery disease, arterial hypertension and arrhythmias.
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The close monitoring of cardiac safety and diagnosis of early cardiotoxicity were based on standards
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proposed by the Polish and European experts [15,16]. All episodes of ADHF had to be diagnosed based on the occurrence of resting typical clinical symptoms and signs of acute heart failure with a concurrent reduction in
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LVEF by at least 10 percentage points versus the baseline value. 2.4. Statistical methods
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Epidemiological data were expressed as percentages of patients’ population. The doses of anthracyclines were presented by median and quartiles. Comparisons between three treatment subgroups were performed using chi^2 tests (for nominal variables) and analysis of variance (for continuous variables). The value of the tests probability level p65 years) and thus there were frequent age-related concomitant cardiovascular diseases. Every third patient had a history of coronary artery disease. In addition, 70 patients (subgroup A) had the baseline contraindications for conventional doxorubicin due to recognised heart
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ACCEPTED MANUSCRIPT failure with preserved (LVEF greater than or equal to 50%) or reduced (LVEF below 50%) left ventricular systolic function. Nevertheless, about half of the observed patients received conventional doxorubicin at the beginning of anticancer treatment (subgroup B and C).
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Out of 138 observed patients, a majority (95 patients; 68.84%) finished treatment in accordance with the planned algorithm. In those patients, there were no interruptions in the administration of consecutive courses of
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chemotherapy. In 14 patients (10.14%), chemotherapy was discontinued due to detected progression of the lymphoma disease (Table 2). In another 29 patients (21.01%) premature termination of chemotherapy was necessary due to complications: in 11 patients (7.97 %) due to cardiotoxicity and in the remaining 18 patients
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(13.04 %) due to other complications or unforeseen events (Table 2). Fourth deaths were noticed in the study: two death related to lymphoma disease, one unexplained sudden death, one cardiac death as a direct consequence
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of cardiotoxicity.
Although treatment subgroups A, B and C were very different from each other in cardiovascular
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characteristics (Table 1), no significant difference in the incidence of ADHF was found between them (Table 2).
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All three scenarios for using of theoretically safer liposomal doxorubicin had similar risk of anticancer treatment failure due to serious cardiotoxicity. There was no significant increase in the incidence of ADHF, even if
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liposomal doxorubicin was applied after conventional form in dose ≥200mg/m2 or if earlier signs of iatrogenic myocardial damage was recognised (subgroup B and C).
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The logistic regression analysis revealed that the administered lifetime cumulative doses of conventional and liposomal doxorubicin seem to be insignificant for the occurrence of new episodes of ADHF (OR=0.85; 95%CI: 0.66 - 1.10; p=0.22 for each 50mg/m2) (Table 3). We analyzed all 3 treatment groups together – they are all patients with abundancy of cardiovascular risk factors treated in curative attempt with doxorubicin based therapy, reflecting the real life situation. The univariate logistic regression demonstrated that ADHF may be associated with a history of atrial fibrillation (Table 3).
4. DISCUSSION 4.1. Cardiac morbidity in patients treated with liposomal doxorubicin Optimal treatment of aggressive lymphoma patients with concomitant cardiovascular diseases, is a challenge, as the standard of care usually includes anthracycline-based regimens. According to Polish cardio-
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ACCEPTED MANUSCRIPT oncology recommendations, modification of treatment should be considered
- liposomal doxorubicin is
potentially one of the most efficient methods of primary cardioprotection. It’s role in the treatment of metastatic breast cancer, especially in women treated earlier with anthracyclines and in women with significant risk factors
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for the development of heart failure is well-established. The aim of using liposomal anthracyclines is to prevent
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or (at least) minimise the risk of both early and late cardiovascular complications. Although one may expect the
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same effect on cardiovascular system in lymphoma patients, the efficacy of liposomal doxorubicin remains an open issue. Bigger “liposomal” particles may not penetrate equally well to isolated lymphoma cells, before their presence causes inflammation resulting in “leaky” capillaries. Therefore, in the absence of randomised non
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inferiority studies, although less cardiotoxic, liposomal doxorubicin cannot be recommended in lymphoma patients without cardiac risk factors.
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Harris et al. [17] in its randomised trial in metastatic breast cancer compared the efficacy and safety of monotherapy with conventional doxorubicin or liposome-encapsulated doxorubicin. Cardiotoxicity was observed
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in 29% of patients receiving conventional doxorubicin and 13% of patients treated with liposomal doxorubicin
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(p=0.0001). The cardiotoxicity of conventional doxorubicin was significantly higher despite a lower cumulative dose administered compared to liposome-encapsulated doxorubicin: 570mg/m2 versus 785 mg/m2 (HR=3.48 ;
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95%CI: 1.79 – 6.78). In line with the study protocol, endomyocardial biopsies were also performed in selected patients. Cardiac damage with a score of at least 2.5 according to the Billingham scale was found in 71% of patients treated with conventional doxorubicin versus 26% receiving the liposomal formulation (p=0.02). The
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third grade according to the Billingham scale was observed only in patients receiving conventional doxorubicin. Such a result of biopsy means that more than 35% of cardiomyocytes in the biopsy tissue were considered abnormal. No patient treated with liposome-encapsulated doxorubicin had similar results. The occurrence of ultrastructural changes in cardiomyocytes seemed to be correlated with the risk of development of symptomatic heart failure in patients receiving conventional doxorubicin. It becomes reasonable and clear that liposomal doxorubicin is a good therapeutic option for patients with a history of cardiac disorders when each additional risk factor (for example toxins like anthracyclines) may be a trigger for progression of heart insufficiency.
The development of acute decompensated heart failure (ADHF) seems to decide significantly about unbeneficial overall survival in patients receiving anticancer therapy (no chance for continuation of oncological treatment, high risk of cardiac death, low quality of life). Further proof for the efficacy and safety of liposomal dixorubicin comes from Batist et al. [18] randomised trial, published in 2001. The incidence of cardiotoxicity
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ACCEPTED MANUSCRIPT was significantly higher in patients receiving conventional doxorubicin: 6% vs. 21% (p=0.0001). There were five cases of symptomatic heart failure, all in the conventional doxorubicin study arm (p=0.02). The analysis of a subgroup of patients with at least one heart failure risk factor showed that women treated with liposomal
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doxorubicin had a 90% lower relative risk of cardiotoxicity.
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In order to analyse the role of liposomal anthracyclines in the treatment of lymphomas, reference can be made to seven recent publications: five exploring the potential benefit of non-pegylated liposomal doxorubicin (NPLD) and two - pegylated liposomal doxorubicin (PLD): trials from Luminari et al. [19], Corazzelli et al.
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[20], Mian et al. [21], Rohlfing et al. [22], Wasle et al. [23], Schmitt et al. [24], Oki et al. [25].
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In the analysed lymphoma studies, the number of patients treated with liposomal doxorubicin ranged from 21 to 326 [19-25]. In each case, the efficacy of liposomal doxorubicin was demonstrated to be comparable to that of conventional doxorubicin. In the course of administration of liposomal doxorubicin chemotherapy,
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cardiac deaths were incidental. In our observation, one cardiac death and one sudden death due unknown cause
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occurred, similarly as in other studies: one cardiac death in the Oki et al. study (1.25%), one death in the Schmitt et al. study (4.8%), four cases in the Mian et al. observation (2.7%) and three cardiac deaths in Rohlfing’s
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observation which due to a small study population (23 patients) resulted in the high 13% mortality [21,22,24,25].
In lymphoma patients the overall incidence of cardiotoxicity was between 4.8% and 36% , hence the
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risk seems to be higher than in women with metastatic breast cancer (4%-13%). Cardiotoxicity risk is definitely correlated with the pre-existing cardiovascular status of the patients (lymphoma patients are older compared to breast cancer), as demonstrated by Corazzelli et al. and Wasle et al. [20,23]. The cited authors implemented the different definitions of cardiotoxicity so a direct comparisons of the results of their studies may be difficult. The definition used in our study is clinically crucial for the prognosis of lymphoma patients as well as in all cardiac patients [26]. The efficacy of treatment of ADHF is expensive and not satisfactory. A good question is how to plan anticancer therapy to avoid new episodes of ADHF especially in patients with a history of cardiovascular diseases.
It should be highlighted that in comparison of subjects from other studies, our patients were in significantly more dangerous cardiac clinical situations due to a number and advance of concomitant
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ACCEPTED MANUSCRIPT cardiovascular diseases (see table 1). Many of them could not receive anthracycline-based chemotherapy in many oncological centers. Even treatment with liposomal doxorubicin may lead to complications such infections, hematological abnormalities and subclinical cardiotoxicity which can influence on development of
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ADHF [27]. The identification of optimal candidates for treatment with liposomal doxorubicin is needed,
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because this drug is significantly more expensive than conventional form. Our study is the only one which
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includes an in-depth analysis of the risk of clinically significant cardiotoxicity for liposomal doxorubicin. It is the first time, when atrial fibrillation was identified as an important risk factor.
We observed no relationship between total dose of doxorubicin and the risk of ADHF which seems to
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be unique in the current medical literature. In our opinion this result was possible thanks to the replacement of the conventional doxorubicin by liposomal form. This clinically positive effect can be explained by the several
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important facts: a) liposomal doxorubicin compared with the conventional form causes significantly less structural damage in the myocardium therefore it may be significantly safer even in patients with serious preexisting cardiovascular diseases; b) only significantly higher dose of liposomal doxorubicin may be responsible
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for the development of heart failure, the latest ESC Position Paper indicates that a dose > 900 mg/m2 correlates
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with the 2% prevalence of heart failure [14]; c) previous published observations showing the importance of anthracycline cumulative doses come from the era when modern cardiac treatment was not used, while all of our
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patients received optimal treatment recommended by ESC that could significantly reduce the cardiotoxic effect of chemotherapy [28].
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4.2. Prior administration of conventional doxorubicin and risk of cardiac damage progression A relapse of cancer in patients previously treated with conventional doxorubicin is always problematic when anthracyclines still remain the best therapeutic option. Our subgroup C represents this specific clinical situation. In each such case, there occurs a question about the impact of the maximum cumulative lifetime dose of conventional doxorubicin. Observations carried out on children’s populations indicate that from the point of view of cardiotoxicity risk (congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities), the important threshold is a conventional doxorubicin dose of 250 mg/m2 [29]. The observed population consisted of very young people with no cardiac conditions at onset, no concomitant diseases and a diagnosis of different types of cancer (14358 patients with leukaemia, brain cancer, Hodgkin's lymphoma, nonHodgkin's lymphoma, kidney cancer, neuroblastoma, soft tissue sarcoma, or bone cancer). In the population of older patients (median age above 50 years) with aggressive non-Hodgkin's lymphoma (NHL) a significant risk
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ACCEPTED MANUSCRIPT of adverse cardiovascular events (asymptomatic cardiac dysfunction, symptomatic heart failure and cardiac deaths) was demonstrated for a dose higher than 200mg/m2 [30]. Some experts indicate the dose of 200mg/m2 as important risk factor for later cardiotoxicity [31].
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According to the international expert consensus [32], following the administration of a cumulative dose of 240 mg/m2 of conventional doxorubicin, echocardiography monitoring with the assessment of LVEF and GLS
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(global longitudinal strain) and measurement of cardiac troponin concentration is required prior to the administration of each consecutive 50 mg/m2 of conventional doxorubicin. The recommendation is based on the latest observations in which new diagnostic methods reveal major cardiac injuries at relatively low doses of
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conventional doxorubicin [33]. In the study cited, patients aged 19 to 80 years (median age 50 years) received from 50 to 375mg/m2 of doxorubicin as a treatment for breast cancer, lymphoma or leukaemia. Within six
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months significant adverse changes were observed in such parameters as left ventricular end-systolic volume, left ventricular strain, pulse wave velocity, LVEF. The outcome was unrelated to age, gender, race, anthracycline
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administration technique, comorbidities or the histopathology of cancer. The observed subclinical cardiovascular
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damage may result in highly adverse cardiovascular events in distant future. A new question appear how to protect myocardial tissue whew a subclinical cardiotoxicity is suspected or recognized. How to continue of
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chemotherapy in such "vulnerable" patients.
In our study, a high percentage of patients (47.1%) had started anticancer treatment with conventional
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doxorubicin. It seems to be important for daily practice because already the first administered dose of conventional doxorubicin may cause significant changes in cardiomyocytes [34]. Initially, cardiomyocyte abnormalities remain mostly asymptomatic but as the dose increases, progressive structural and functional damage of the myocardium occurs. Clinical symptoms may manifest still during treatment or a few months or even years after its completion, depending on the individual sensitivity [35]. We confirmed that this effect was not seen in our study, because during active administration of chemotherapy with liposomal doxorubicin, the frequency of ADHF was not higher in the patients who were treated earlier with conventional doxorubicin (subgroups B and C). The 2016 ESC Position Paper suggests that cancer patients with low baseline risk but scheduled for doses >250-300mg/m2 may be candidates for cardioprotective actions and surveillance should be considered after 200mg/m2 of doxorubicin [14]. The 2016 ASCO guidelines recommends that prophylactic strategies may
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ACCEPTED MANUSCRIPT be incorporated, including use of liposomal doxorubicin, in patients planning to receive high-dose anthracyclines (eg. doxorubicin ≥ 250 mg/m2) [36]. In our patients from subgroup B the frequency of ADHF was not significantly higher because just these
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patients with cardiovascular risk factors had meantime modified scheme of chemotherapy (replaced conventional
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by liposomal doxorubicin) after administration 200mg/m2 of conventional doxorubicin or due to noticeable
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signs suggesting unacceptable cardiac damage. It would be clinically worth to define the optimal moment to change the form of doxorubicin when we need to give more than 4 cycles of chemotherapy (cumulative dose of doxorubicin certainly higher then 200-240 mg/m2). It should be analysed in the future, because this proposed
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strategy has a chance to guarantee better prognosis of patients with high baseline cardiovascular risk.
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4.3. Significance of atrial fibrillation (AF) as a possible risk factor in cardio-oncology Atrial fibrillation (AF) is the most common type of cardiac arrhythmia associated with heart failure
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[37]. It is still debatable, how frequently is AF a cause of heart failure with reduced LVEF (tachycardia-induced
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cardiomyopathy). AF significantly increases mortality, particularly in patients with cardiac comorbidities [38,39]. In patients with AF both structural [40, 41] and electrical remodelling [42,43] is observed. From a
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pathophysiological point of view heart failure with AF is a separate entity [44]. Our findings seem to confirm this phenomenon in special cardio-oncology group of patients. Understanding of the cardiotoxicity observed in our study becomes easier when the heart abnormalities
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found in patients with AF are compared and linked with early changes observed after the administration of anthracyclines (especially conventional formulations). Administration of anthracyclines increases afterload and rigidity of blood vessels followed by heart wall thickening and an increase in the left ventricular dimension/volume [45,46]. The subsequent LV dilatation may be associated with bicuspid valve regurgitation or dysfunction [47]. AF may precipitate such a cascade of changes and may contribute to the occurrence of ADHF. It should also be noted that the pathomechanisms responsible for the development of AF also include abnormalities in calcium homeostasis, ion channel dysfunctions, atrial fibrosis, dysfunctions of the autonomous nervous system and oxidative stress [48]. The same mechanisms are mentioned to explain the pathophysiology of anthracyclines cardiotoxicity. In the future, adequate cardio-oncology strategies may be required for patients with AF.
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ACCEPTED MANUSCRIPT 4.4. Limitations of the study The first important limitation of our observation is the lack of randomization. However, we believe that liposomal anthracycline therapy should be reserved for patients with a history of significant heart diseases.
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Under this assumption, the procedure of randomization seems to be irrational because so ill patients cannot receive conventional doxorubicin. According to the Polish legal regulations, patients with serious heart disease
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can get liposomal doxorubicin. Other patients must get a conventional doxorubicin, but if they receive at least 200mg/m2 of conventional doxorubicin or experience iatrogenic cardiac dysfunction then also become entitled to receive liposomal doxorubicin. These criteria seem very reasonable. Our work confirms the low incidence of
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ADHF in so problematic population.
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The second serious limitation of our work is the lack of long-term follow-up. We established this on purpose because in cardiac patient with cancer, the primary task is to secure them through the active anticancer treatment. Naturally, our patients are still observed. A next publication will include a long-term analysis
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(assuming at least a five-year observation), together with the assessment of progression-free survival, analysis of
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survival free of cardiac events and analysis of overall survival. But it should be highlighted that every day oncologists and haematologists have to consider how to use liposomal doxorubicin, which dose for which
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patient. It is an introduction to personalized oncology for patients required anthracycline-based chemotherapy and thus this current publication is unique in the available literature.
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The third limitation is the fact that the observed low incidence of ADHF makes the identified cardiac risk factors had a relatively wide confidence interval and the multivariate analyses were impossible. Our study indicates a possible problematic situation of patients with a history of AF and other cardio-oncological researchers should focus on their outcome. However the significance of predictive value of genetic predisposition for cardiotoxicity is still undefined but should not be forgotten. One thing is for sure that our implemented three schedules of chemotherapy with cardioprotective use of liposomal doxorubicin had the same risk of ADHF occurrence and each of them needs further observation and possible validation. Now they meet current recommendations of the main scientific societies [14,36]. 5. CONCLUSIONS In terms of cardiac safety, liposomal doxorubicin seems to be a rational therapeutic option for patients with lymphomas and concomitant cardiovascular conditions. It can be safely used after the application of some
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ACCEPTED MANUSCRIPT cycles of conventional doxorubicin even if early signs of cardiac damage are observed. The strategy for administration of conventional/liposomal doxorubicin should be strongly based on risk of heart failure. The replacement conventional doxorubicin by non-pegylated liposomal form can guarantee that a lifetime cumulative
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doxorubicin dose will become insignificant for serious cardiotoxicity and chemotherapy will be completed in the
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scheduled time. It should be borne in mind, however, that new episodes of ADHF have been observed during
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this type of therapy and patients with a history of atrial fibrillation may be at a particularly high risk. There is a
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need to define patients with anticancer benefit significantly higher than cardiac risk.
6. ACKNOWLEDGEMENT
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The study was conducted and supported by the Polish Lymphoma Research Group and the East European Branch of International CardiOncology Society.
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Conflict of interest: S. Szmit, W. Jurczak, JM. Zaucha- they have received honoraria for lectures on the
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ACCEPTED MANUSCRIPT Table 1. Characteristics of observed patients with significant cardiovascular disorder regarding each scenario of chemotherapy.
paroxysmal persistent Other types of arrhythmias Valvular heart disease Diabetes mellitus Obesity (BMI ≥ 30 kg/m^2)
Patients with coexisting
Patients receiving
diagnosis of heart
cardiovascular disorders
liposomal doxorubicin
failure receiving only
treated sequentially with
as second line
liposomal doxorubicin
conventional and
as first line
liposomal doxorubicin as
first line with
chemotherapy
first line chemotherapy
conventional
350 250 - 400 59 (42.8%) 79 (57.2%)
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doxorubicin 17 (12.3 %)
200 150 - 250
200 100 - 200
300 200 - 400
400 300 - 400
550 500 - 600
30 40
25 26
4 13
0.18
69.5 ± 11.6
60.8 ±15.3
54.5 ± 12.8
65 years) Baseline LVEF (%)
Subgroup B
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Number of patients (%) Dose of liposomal doxorubicin (mg/m2): Median Quartiles Lifetime cumulative dose of all types of doxorubicin (mg/m2): Median Quartiles Gender Female Male Age (years)
Subgroup A:
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All patients
0.57 0.16
0.01 0.67
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Table 2. Number of patients with serious events as a cause of premature discontinuation of chemotherapy in each treatment subgroup.
Lymphoma disease progression
Subgroup C
N= 138 (%)
N=70 (%)
N=51 (%)
N=17 (%)
18 (13.04 %) #
12 (17.14 %)
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5 (9.8 %)
SC R
5 (7.14 %)
11 (7.97 %)*
5 (7.14 %)
14 (10.14 %)
p-value
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Subgroup B
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Other complications
Subgroup A
1 (5.88 %)
4 (7.84 %)
2 (11.76 %)
3 (5.88 %)
6 (35.29%)
0.82
0.32
0.001
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Acute decompensated heart failure
All patients
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Legends: * one episode complicated by cardiac death # one sudden death due to unexplained reason
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Table 3. The analysis for the relationship between ADHF occurrence and all possible risk factors including the lifetime
Lifetime cumulative dose of all types of doxorubicin
p-value
0.66 - 1.10
0.22
1.07
0.31 - 3.74
0.91
0.48
0.12 - 1.9
0.29
1.54
0.3 - 7.9
0.6
0.39
0.08 - 1.92
0.24
0.4
0.11 - 1.44
0.16
2.91
0.54 - 15.8
0.21
3.95
0.9 - 17.32
0.07
7.56
1.57 - 36.48
0.01
0.69
0.08 - 5.9
0.74
2.02
0.22 - 18.81
0.53
1.63
0.44 - 5.99
0.46
0.85
0.17 - 4.26
0.85
0.85
SC R
for each 50mg/m2
95% CI
IP
OR
Older age ( > 65 years) Female vs male Baseline LVEF
