Leukemia & Lymphoma, 2014; Early Online: 1–14

© 2014 Informa UK, Ltd.

ISSN: 1042-8194 print / 1029-2403 online
DOI: 10.3109/10428194.2014.894187

REVIEW

The more patients you treat, the more you cure: managing cardiotoxicity
in the treatment of aggressive non-Hodgkin lymphoma
Pier Luigi Zinzani1, Massimo Federico2, Stefano Oliva3, Antonello Pinto4, Luigi Rigacci5, Giorgina Specchia6,
Alessandra Tucci7 & Umberto Vitolo8
1Institute of Hematology and Medical Oncology “L. e A. Seràgnoli”, University of Bologna, Italy, 2Medical Oncology,
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University of Modena and Reggio Emilia, Italy, 3Cardiology Unit, National Cancer Institute IRCCS “Giovanni Paolo II”, Bari, Italy,
4Hematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione “G. Pascale”, IRCCS,

Naples, Italy, 5Hematology Department AOU Careggi, Florence, Italy, 6Hematology and Stem Cell Transplantation,
Department of Eergency and Organ Transplantation, University Aldo Moro, Bari, Italy, 7Hematology Division, Spedali Civili,
Brescia, Italy and 8Department of Oncology and Hematology, San Giovanni Battista Hospital, Torino, Italy

care for elderly patients with diffuse large B-cell lymphoma

Abstract
(DLBCL), the most common type of aggressive lymphoma,
Athracycline-based regimens remain the gold standard for
the treatment of lymphomas, even if their use can be limited and its efficacy has also been confirmed in younger patients
by associated cardiac toxicity, especially in elderly patients. [3,4]. Overall, anthracyclines are currently a necessary,
Although most patients with aggressive non-Hodgkin and not dispensable, component in the management of
For personal use only.

lymphoma (NHL) are elderly, they may envisage long-term life aggressive NHL.
expectancy. Thus, there is a need for therapeutic strategies The main setback of anthracycline therapy is toxic-
that can overcome the impact of anthracycline cardiotoxicity. ity, especially in elderly patients. Cardiologic toxicity
A better understanding of its pathogenetic mechanisms, induced by doxorubicin remains a concern for clinicians,
the identification of risk factors of cardiac dysfunction, and because the cumulative toxicity of anthracyclines is dose
appropriate therapy should prove useful in this setting. A limiting and irreversible [5,6]. A dose of doxorubicin of
comparable efficacy and reduced cardiotoxicity even in frail and 450–550 mg/m2 is traditionally considered the lifetime
elderly patients have been shown with the use of non-pegylated cumulative dose limit [7,8].
liposomal doxorubicin, when substituted for conventional Today the mean age of patients with aggressive lymphoma
doxorubicin in standard chemotherapy regimens for NHL. In is 65 years, and about 60% of patients are over 60 years of
the coming years, the goal will be to apply these advancements age; the progressive lengthening of life expectancy will prob-
to the treatment of patients with NHL, to ensure adequate ably increase their numbers in the future [9,10]. The lower
therapy in patients currently denied conventional intensive complete remission (CR) rate in elderly patients has been
chemotherapy because of age or comorbidities. linked to the frequent administration of less intensive non-
Keywords: Anthracycline, liposomal drugs, cardiotoxicity, anthracycline-containing therapy, because those patients
aggressive NHL who are given anthracyclines appear to display similar
tumor chemosensitivity regardless of age [11,12]. Most likely,
a significant improvement in the general outcome of these
Introduction patients might be observed if more intensive anthracycline-
Introduced in the 1960s, anthracyclines remain a corner- based regimens could be administered.
stone in the treatment of lymphomas. Doxorubicin, the To date, different strategies have been attempted to
first antitumor antibiotic, was initially used as a single reduce the cardiotoxicity of anthracyclines, including the
agent for the therapy of non-Hodgkin lymphoma (NHL) design of chemotherapy regimens with reduced drug doses
and subsequently combined with alkylators and other [13–15], the addition of cardioprotectants [16,17], the use of
chemotherapeutics, showing a high efficacy [1,2]. Today, different dose schedules [18] and the development of doxo-
the R-CHOP combination (rituximab, cyclophosphamide, rubicin analogs with an assumed improvement in the safety
doxorubicin, vincristine, prednisone) is still the standard of profile [19].

Correspondence: Prof. P. L. Zinzani, Institute of Hematology and Medical Oncology “L. e A. Seràgnoli”, via Massarenti 9, 40138 Bologna, Italy.
Tel: ⫹ 39-0516363680. Fax: ⫹ 39-0516364037. E-mail: pierluigi.zinzani@unibo.it
Received 17 October 2013; revised 4 February 2014; accepted 7 February 2014

1
 2 P. L. Zinzani et al.

More recently, liposomal formulations of doxorubicin anthracycline cardiotoxicity have not been fully elucidated.
have been developed with the aim of reducing the drug’s The oxidative stress hypothesis has been very popular in
cardiotoxicity while retaining its antitumor effect [20,21]. the past decade; several studies have showed that anthra-
Non-pegylated liposomal doxorubicin (NPLD) has been cyclines can promote reactive oxygen species formation
shown to have a smaller volume of distribution and a pref- and lipid peroxidation, but the apparent lack of protection
erential distribution to the liver, spleen and the lymphatic provided by simple antioxidants such as vitamin E [36]
system, with reduced drug delivery to the myocardium, points to the existence of alternative mechanisms of
compared with conventional doxorubicin [22,23], resulting myocardial damage [5,37]. The relevance of myofibrillar
in reduced myelosuppression and improved gastrointestinal deterioration and intracellular calcium dysregulation,
and cardiac safety [24]. When substituted for conventional together with other potential mechanisms of cardiotoxic-
doxorubicin in the CHOP regimen (COMP), with or without ity, and the involvement of other cell types beside myo-
the addition of R, NPLD has been shown to be effective cytes, including fibroblasts and endothelial cells, has been
in newly diagnosed aggressive NHL [25] as well as in suggested. Furthermore, doxorubicin-associated cardiac
the elderly [26,27] and patients with high-risk disease [28]. toxicity may be mediated, at least in part, by changes in
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Anti-lymphoma activity and reduced cardiotoxicity have the high-energy phosphate pool, endothelin-1 levels and
also been demonstrated by the new aza-anthracene- disturbances of myocardial adrenergic signaling [38].
dione pixantrone dimaleate, whose structure lacks the These mechanisms do not fully explain the individual
5,8-dihydroxy substitution groups implicated in anthracy- variability in cardiotoxicity after anthracycline treatment. In
cline-induced cardiotoxicity [29,30]. humans, the presence of a genetic component is suggested by
A better understanding of the mechanisms of cardiotoxic- the wide interindividual variation of the anthracycline dose
ity of anthracyclines, coupled with the recognition of patients at which cardiotoxicity is observed. However, the existence
with high-risk disease and of methods to optimally manage of gene variants predisposing to anthracycline-induced
and monitor cardiac toxicity, should help in the coming cardiotoxicity has not been addressed in clinical studies.
years to fully exploit these drugs’ potential, further improv- Wojnowski et al. provided the first evidence for the existence
ing the efficacy and safety of anthracycline-based regimens of gene variants associated with an increased sensitivity to
in patients with NHL. cardiac effects of anthracyclines, genotyping and testing for
For personal use only.

association with the clinical phenotype a total of 206 vari-

ants from 82 genes involved in the metabolism of reactive
Cardiotoxicity of anthracyclines
oxygen species, drug transport and metabolism, DNA repair,
Anthracyclines are known to cause both short- and long- endothelial physiology, the renin–angiotensin–aldosterone
term cardiotoxicity, including potentially fatal congestive system, muscle contraction and structure, inflammation and
heart failure (CHF). However, acute cardiac toxic effects [31] cell cycle [39].
generally resolve, and the long-term risk of CHF associated The recognition of genetic and proteomic markers of
with doxorubicin use remains the main clinical concern. individual patients’ susceptibility to the cardiotoxic effects
Clinically, the long-term myocardial dysfunction induced of doxorubicin could represent useful assistance in improv-
by anthracyclines, associated with dilated cardiomyopathy ing the safety of anthracycline treatment, helping to identify
and left-sided CHF, occurs 2–5 years after treatment (but patients with high-risk disease [5,40–42]. Moreover, gender
cases have been reported up to 20 years after therapy), and difference has been mentioned as one of the risk factors
has a poor outcome: a 5-year mortality rate of 50% has been in the toxic effects of doxorubicin, with a reported signifi-
reported in these patients [32]. CHF after anthracyclines is cantly higher risk of cardiotoxicity in females compared
generally, but not always, irreversible [33,34]. with males [43].
Historically, concerns about anthracycline cardio- A particular aspect of anthracycline-associated car-
toxicity date from the first years of use, and an overall incidence diotoxicity is the late onset of cardiac adverse events in
of doxorubicin-induced CHF was retrospectively reported long-term survivors of childhood cancers. Cardiotoxic-
in 2.2% of cases among 4018 patients treated with the drug ity may manifest years or decades after anthracycline
[8]. Subsequent prospective assessments showed that the administration in childhood, causing an increasing risk of
rate of doxorubicin-associated CHF was related to the cumu- heart failure, other cardiovascular disease or stroke [44]. In
lative dose of the drug (5% at a dose of 400 mg/m2, 16% at 500 this population of patients, no safe dose of anthracyclines
mg/m2 and 26% at 550 mg/m2) [7]. has been reported, and an increased risk of ventricular
In addition to clinical CHF, anthracycline-based che- dysfunction has been suggested for doses of doxorubicin
motherapy may be associated with an insidious subclinical as low as 100 mg/m2 [45]. Dilated cardiomyopathy often
cardiomyopathy, reported at least 5 years after treatment progresses to a restrictive cardiomyopathy in these patients
in 28% of patients with NHL receiving doxorubicin-based [46]. The mechanisms underlying this late-onset anthra-
chemotherapy [35]. In these patients, other factors that stress cycline cardiotoxicity in children are poorly recognized,
the heart, such as hypertension and developing coronary but are probably different in part from those observed in
disease, may precipitate the cardiac damage induced by adult patients [46,47]. Blanco et al. [42] demonstrated that
anthracyclines, causing the onset of overt CHF. patients with CBR3 (cytosolic carbonyl reductase 3, which
Despite more than four decades of investigation, mediates the reduction of anthracyclines to cardiotoxic
the pathogenic mechanisms responsible for long-term alcohol metabolites) V244M homozygous G genotype
 Cardiotoxicity and aggressive non-Hodgkin lymphoma 3

exposed to low- to moderate-dose anthracyclines are at in tissue Doppler parameters of diastolic function was
increased risk of cardiomyopathy, even at cumulative expo- observed in both arms.
sures of as little as 101–150 mg/m2. These results could lead In young patients with good-prognosis DLBCL, the
to establishing enhanced surveillance and/or prevention recently published update, with a 6-year follow-up, of
strategies for survivors of childhood cancer at increased the MInT (MabThera International Trial), enrolling 824
risk of cardiomyopathy. young patients, reported improved long-term EFS and OS
outcomes with the addition of R compared with CHOP
or CHOP-like regimens alone [61]. In this study, the rates
The role of anthracycline-based regimens
of grade 3–4 cardiac adverse events were 1% and 2% for
in aggressive non-Hodgkin lymphoma
the chemotherapy and the chemotherapy plus R arms,
The CHOP regimen, introduced in 1973 [48], has been the respectively. Two deaths from myocardial infarction were
standard therapy for aggressive lymphomas since 1986 [49], recorded, both in the CHOP-like chemotherapy arm [4].
and similar CR rates, progression-free survival (PFS) and Overall, the introduction of immunochemotherapy does
overall survival (OS) were demonstrated for this scheme as not appear to have changed the impact of cardiotoxicity
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for more complicated and toxic regimens [50]. on patients with lymphoma receiving anthracycline-based
Early experiences with the CHOP regimen in aggressive regimens, but these studies were not designed to assess
lymphomas reported rates of 20% of patients suffering from long-term cardiotoxicity.
a cardiac event after 1 year of treatment [51]. In a cohort of Alternative anthracycline-based regimens have been
135 patients (median age, 59 years), 14 (10.3%) had clini- studied and continue to be under investigation especially
cal signs of CHF attributable to doxorubicin therapy. Three in younger patients. In patients with good-risk disease (an
patients (2.2%) died from a cardiac event during the year age-adjusted International Prognostic Index [aaIPI] score
of treatment and 25 patients (18.5%) had a decreasing left of 0 or 1), the ACVBP (doxorubicin, cyclophosphamide,
ventricular ejection fraction (LVEF) [51]. Doorduijn et al. vincristine, bleomycin, prednisone) combination with
reported 17 (4.4%) cardiac-related deaths in a population of sequential consolidation achieved rates of 5-year EFS
389 elderly patients (mean age, 73 years; range, 65–90 years) and OS of 82% and 90%, respectively [62]. Based on these
with aggressive NHL receiving CHOP [52]. results, the phase 3 randomized LNH03-2B trial compared
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Attempts to improve the results of CHOP chemotherapy 6–8 cycles of R-CHOP with ACVBP plus R in young patients
were made subsequently, in the pre-R period, with the with good-risk DLBCL [63]. Three-year estimates of EFS,
reduction of the inter-treatment interval and the addition PFS and OS were 81%, 87% and 92%, respectively, in the
of etoposide [53–56], obtaining controversial results. The R-ACVBP group, all significantly higher than in the R-CHOP
addition of etoposide (CHOEP-21 and CHOEP-14 regimens) group. However, the rate of serious adverse events was 42%
did not result in significantly higher rates of cardiotoxicity in the R-ACVBP arm versus 15% with R-CHOP, making the
[53,56]. However, long-term cardiotoxicity was not evalu- benefit of more intensified treatments doubtful in young
ated in these studies, and reported rates relate only to the patients at low risk. No differences in cardiac-related toxic-
therapy period. ity were observed between the two arms (0–1% grade ⱖ 3
The addition of R to CHOP-21 (R-CHOP-21) came after events).
the demonstration of the activity of this agent in aggressive Also in the rituximab era, for young patients with high-
B-cell lymphomas, leading to several studies that confirmed risk aggressive B-cell lymphoma, high-dose therapy fol-
the superior efficacy of R-CHOP over CHOP in patients with lowed by autologous hematopoietic stem cell transplant
DLBCL, setting this as the new standard of care in both young (ASCT) was evaluated as part of first-line therapy, in an
and elderly patients [3,4,57,58]. The results from the first attempt to improve the response rate and decrease the
report of direct comparison between R-CHOP and CHOP relapse rate. The results have been contradictory. Whereas
by GELA (Groupe d’Etude des Lymphomes de l’Adulte) in the randomized phase 3 trial DSHNHL (German High
elderly patients with DLBCL showed a 5-year PFS of around Grade Non-Hodgkin’s Lymphoma Study Group) 2002-1
50% in the R-CHOP arm, compared with 28% in the CHOP showed that a conventional R-CHOEP-14 regimen was not
arm, with a significant improvement in OS as well [58]. The inferior and was associated with significantly fewer toxic
RICOVER (R with CHOP over age 60 years) trial tested the effects compared with high-dose therapy (MegaCHOEP)
value of the addition of rituximab to CHOP-14 in elderly plus R followed by repetitive ASCT [55], in young patients
patients with DLBCL. Six cycles of R-CHOP-14 significantly with high-risk DLBCL enrolled in the DLCL04 trial an
improved event-free survival (EFS), PFS and OS over six intensified treatment including ASCT significantly reduced
cycles of CHOP-14 [59]. the risk of progression, with a 3-year PFS of 70% compared
The addition of R to CHOP was reported not to increase with 59% of patients receiving R-dose-dense standard
the risk of cardiotoxicity in patients with NHL [3,58]. In therapy only [64]. On the whole, the benefit of upfront
a study by Kilickap et al., specifically designed to assess ASCT remains controversial, but this approach may be
the impact of the addition of R on doxorubicin-induced considered for selected patients with high-risk disease who
cardiotoxicity in 61 patients with B-cell NHL (median age, achieve a partial response (PR) or CR with a dose-intense
50 years) [60], none of the patients developed clinically or dose-dense regimen.
evident CHF. Parameters of systolic function did not The efficacy and toxicity of anthracycline-based regimens
significantly change in any patient, and a similar decrease in aggressive NHL are summarized in Table I.
 4 P. L. Zinzani et al.

Table I. Anthracycline-based regimens in untreated aggressive non-Hodgkin lymphoma*.

Patients
Reference (n) Eligibility for D Treatment Dose of D Outcome Cardiac events
Fisher et al., 1993 [50] 225† Median age (range): 56 years CHOP ⫻ 8 50 mg/m2 CR 44% NA
(15–79) TTF 41% at 3 years
No marked impairment of OS 54% at 3 years
cardiac function
Doorduijn et al., 192 Median age (range): 72 years CHOP ⫻ 6–8 50 mg/m2 CR 55% 3% grade 3–4 cardiac
2003 [52] (65–90) PFS 24% at 5 years events; 4% cardiac
LVEF ⱖ 45% OS 22% at 5 years deaths
Pfreundschuh et al., 172 Age ⱖ 61 years and ⱕ 75 years CHOP-14 ⫻ 6 50 mg/m2 CR 76% 5% grade 3–4 cardiac
2004 [53] No marked impairment of EFS 44% at 5 years events
cardiac function OS 53% at 5 years
Pfreundschuh et al., 172 Age ⱖ 18 years and ⱕ 60 years CHOP-14 ⫻ 6 50 mg/m2 CR 78% 0.6% grade 3–4
2004 [56] No marked impairment of EFS 61% at 5 years cardiac events
cardiac function OS 85% at 5 years
Blayney et al., 2003 [54] 88† Median age (range): 52 years CHOP-14-DI ⫻ 6 65 mg/m2 CR NA 7% grade 3–4 cardiac
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(19–77) PFS 41% at 5 years events;

No cardiac comorbidities OS 60% at 5 years 1 cardiac death
Feugier et al., 2005 [58]; 202 Median age (range): 69 years R-CHOP ⫻ 8 50 mg/m2 CR 75% 47% any grade and
Coiffier et al., 2002 [3] (60–80) PFS 54% at 5 years 8% grade 3–4
No cardiac contraindication OS 58% at 5 years cardiac events
to doxorubicin
Pfreundschuh 413 Median age (range): 47 years R-CHOP or NA CR 86% 2% grade 3–4 cardiac
et al., 2006 [4]; (36–55) R-CHOP-like ⫻ 6 PFS 80.2% at 6 years events
Pfreundschuh et al., No cardiac comorbidities OS 90% at 6 years
2011 [61]
Reyes et al., 2005 [62] 318 Median age (range): 46 years ACVBP ⫻ 3 75 mg/m2 CR 93% One late cardiac
(16–60) EFS 82% at 5 years death; no cases
No cardiac contraindication OS 90% at 5 years of CHF
to doxorubicin
Récher et al., 2011 [63] 196 Median age (range): 47 years R-ACVBP ⫻ 4 ⫹ 75 mg/m2 CR 83% 3% any grade and 0%
(18–59) consolidation PFS 87% at 3 years grade 3–4 cardiac
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No cardiac contraindication OS 92% at 3 years events

to doxorubicin
Pfreundschuh et al., 170 Age ⱖ 61 years and ⱕ 75 years CHOEP-21 ⫻ 6 50 mg/m2 CR 70% 4% grade 3–4 cardiac
2004 [53] No marked impairment of EFS 41% at 5 years events
cardiac function OS 46% at 5 years
Pfreundschuh et al., 185 Age ⱖ 18 years and ⱕ 60 years CHOEP-21 ⫻ 6 50 mg/m2 CR 84.9% 3% grade 3–4 cardiac
2004 [56] No marked impairment of EFS 69% at 5 years events
cardiac function OS 833% at 5 years
ACVBP, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone; CHF, congestive heart failure; CHOEP, cyclophosphamide, doxorubicin, vincristine,
etoposide, prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; D, doxorubicin; DI, dose intense; EFS, event-free
survival; NA, not available; NHL, non-Hodgkin lymphoma; OS, overall survival; PFS, progression-free survival; R-, addition of rituximab; TTF, time to treatment
failure.
*If not specified, CHOP and R-CHOP every 3 weeks. Only the actual number of patients treated with the indicated regimen is reported.
†Intermediate or high-grade NHL.

Attempts to overcome anthracycline-associated DLBCL ⬎ 80 years, showing a good efficacy with acceptable
cardiotoxicity toxicity [65].
For a long time it was suggested that the anthracycline epi-
Despite the proven efficacy of anthracyclines, cardiologic rubicin was less cardiotoxic than doxorubicin [66]. Epirubi-
toxicity induced by these drugs remains a concern in the cin may be substituted for doxorubicin in the CHOP regimen
practical management of patients with lymphoma, especially (CEOP), showing a good efficacy in aggressive lymphomas
in elderly and frail patients. [15,67]. Although the Cochrane meta-analysis showed no evi-
Historically, several measures to lessen the cardio- dence of a significant difference in the occurrence of clinical
toxicity of anthracyclines have been tested, including the heart failure between doxorubicin- and epirubicin-treated
modification of duration and frequency of administration, patients, some suggestion of a lower rate of clinical heart
the use of doxorubicin analogs and the addition of cardio- failure in patients receiving epirubicin was reported [19].
protectants such as dexrazoxane. A Cochrane review of Similarly, CIOP (cyclophosphamide, idarubicin, vincristine,
five randomized controlled trials concluded that con- prednisone) and CNOP (cyclophosphamide, mitoxantrone,
tinuous infusion for 6 h or longer significantly reduced the vincristine, prednisone) regimens have been investigated in
risk of clinical heart failure in adult patients [18]. In the patients with NHL, based on the assumed lower cardiotox-
study by Von Hoff et al., a weekly dose schedule of doxo- icity of idarubicin and mitoxantrone. However, results have
rubicin was associated with a significantly lower incidence been conflicting, and although some evidence of equivalent
of CHF compared with the usual three-weekly schedule, therapeutic effect was found for these drugs compared with
but an equivalent efficacy remains to be demonstrated [8]. doxorubicin [68–70], other studies have reported a lower effi-
A decreased dose of CHOP with a conventional dose of R cacy in patients with aggressive lymphomas [71,72], confirm-
(R-miniCHOP) has also been tested in elderly patients with ing CHOP therapy as standard of care for these patients.
 Cardiotoxicity and aggressive non-Hodgkin lymphoma 5

Another anthracycline drug with apparently fewer on these results, a randomized phase 3 trial assessed the
cardiotoxic effects than doxorubicin, pirarubicin (tetra- efficacy and safety of pixantrone versus an investigator’s
hydropyranyl-adriamycin, THP), has been tested in asso- choice of a single agent therapy in 140 patients who had
ciation with cyclophosphamide, vincristine, prednisolone received two or more previous regimens of chemotherapy for
and R in elderly patients with DLBCL. In a phase 2 study, relapsed or refractory aggressive NHL [30]. A significant dif-
3-weekly R-THP-COP resulted in CR and 3-year OS rates ference in response rate was observed in favor of pixantrone
of 63% and 53%, respectively, with no deaths related to (20.0% CR and unconfirmed CR [CRu] vs. 5.7% for pixantrone
the treatment [73]. A randomized study also compared the and alternative drugs, respectively), as well as an increase
CTVP regimen (cyclophosphamide, teniposide, prednisone, of 2.7 and 2.6 months, respectively, in the median PFS and
pirarubicin) with CVP in older patients with aggressive OS times. As for cardiotoxicity, more cardiac adverse events
lymphoma (median age: 75 years). Death during chemo- occurred in the pixantrone treatment group (35.3%) than in
therapy occurred in 21% and 16% of patients in the CTVP the comparator (20.9%), with the majority being asymptom-
and CVP arms, respectively (not significant), but a slightly atic decreases in LVEF (19.1%). One patient’s LVEF in the
longer survival was observed for patients treated with the pixantrone group reversibly reduced to less than 40%. The
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anthracycline-containing regimen (5-year survival rate: change in LVEF values in patients who received pixantrone
26% with CTVP vs. 19% with CVP, p ⬍ 0.05) [74]. Dexrazox- was not associated with clinical evidence of cardiac impair-
ane has been recommended for anthracycline-pretreated ment. Following this study, in May 2012 pixantrone was
patients as a possible means of reducing cardiotoxicity authorized by the EMA for the treatment of adult patients
based on its iron-chelating abilities, which can scavenge with multiply relapsed or refractory aggressive non-Hodgkin
free radicals [16,75]. However, the efficacy of dexrazoxane B-cell lymphoma.
in reducing cardiac adverse events in elderly patients with The efficacy and safety of pixantrone has also been
cardiac comorbidity is not known [76]. Furthermore, some assessed in combination with other drugs in patients with
evidence of a potential risk of secondary malignancies in relapsed/refractory aggressive NHL, including a PSHAP
pediatric patients treated with dexrazoxane and topo- (pixantrone, methylprednisolone, cisplatin and cytarabine
isomerase II inhibitors (such as etoposide and doxorubicin) [ARA-C]) regimen, reporting an ORR of 58%, with a median
recently prompted the European Medicines Agency (EMA) time to progression and an OS of 5.7 months and 14.5 months,
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to recommend the use of this drug only in adult patients respectively [82]. In this study, no clinically significant car-
with advanced breast cancer. diac toxicity occurred. Seven patients (37%) had a decline in
Other cardioprotective agents that have been clinically their LVEF ⱖ 10% from baseline and/or decrease in LVEF to
tested, without definitive conclusions about their efficacy, ⬍ 50%. When evaluated in place of doxorubicin in the stan-
include N-acetylcysteine, phenethylamines, coenzyme Q10, dard CHOP regimen (CPOP) in a phase 1/2 study, pixantrone
combined vitamins E and C and N-acetylcysteine, and l-car- induced an ORR of 73% (47% CR/CRu) with an OS of 17.9
nitine [16]. Single studies have suggested that the use of beta months in 55 patients with relapsed aggressive NHL, four of
blockers and angiotensin-converting enzyme (ACE) inhibi- whom experienced symptomatic cardiac failure [83]. In the R
tors, drugs not able to prevent myocyte damage but improv- era, the results of a direct comparison between the CPOP-R
ing the heart’s compensatory mechanisms, may prevent the and CHOP-R regimens in 124 untreated patients with DLBCL
development of later cardiotoxicity [77,78]. have been recently published [29]. CPOP-R showed a mod-
Recently, the novel aza-anthracenedione pixantrone estly lower response rate than CHOP-R (CR/CRu rate: 75%
dimaleate, specifically synthesized to reduce anthracycline- vs. 84%, respectively) and shorter 3-year OS (69% vs. 85%,
related cardiotoxicity, was reported to be active as single- p ⫽ 0.029), but similar PFS and EFS. Overall, fewer patients
agent therapy in heavily pretreated patients with relapsed with CPOP-R developed grade 3 CHF (0% vs. 6%, p ⫽ 0.120),
or refractory aggressive NHL [30]. Pixantrone is similar in ⱖ 20% declines in LVEF (2% vs. 17%, p ⫽ 0.004) and elevation
structure to anthracyclines and anthracenediones, but lacks in troponin-T (7% vs. 33%, p ⫽ 0.003).
the 5,8-dihydroxy substitution groups thought to be respon- The efficacy and toxicity of anthracyclines other than
sible for the cardiac toxicity associated with anthracyclines, doxorubicin and anthracycline-analog regimens in aggres-
through iron binding, free-radical formation and reduction sive NHL are summarized in Table II.
to cardiotoxic alcohol metabolites, such as doxorubicinol
[79]. Following preclinical studies showing substantially
The role of liposomal anthracycline-based
less cardiotoxicity and superior activity compared to doxo-
regimens in aggressive non-Hodgkin
rubicin and mitoxantrone in animal models, pixantrone has
lymphoma
been tested as a single agent in phase 1–2 studies in patients
with multiply relapsed aggressive NHL [80,81]. A schedule Liposome-encapsulated anthracyclines were designed with
of weekly 85 mg/m2 pixantrone for 3 weeks, every 4 weeks, the intention of reducing the cardiotoxicity associated with
showed encouraging activity (27% overall response rate the use of these drugs while still preserving their efficacy.
[ORR] and 15% CR rate) in 33 patients with aggressive NHL The basic rationale is that encapsulation of anthracyclines
(median age: 66 years) with an adequate safety profile. A sig- in liposome modifies the pharmacokinetics of the drug,
nificant decrease of more than 10% of the LVEF was detected leading to a selective uptake by the tumor, and reduced
in three patients (9%), all pretreated with anthracyclines, clearance, compared with healthy tissues including the
in two cases accompanied by cardiac symptoms [81]. Based myocardium [22,23]. Preclinical studies comparing equal
 6 P. L. Zinzani et al.

Table II. Anthracyclines other than doxorubicin and anthracycline-analog regimens in aggressive non-Hodgkin lymphoma*.
Patients LVEF
Reference (n) Eligibility for A Treatment Drug Outcome post-treatment Cardiac events
Merli et al., 114 Median age (range): R-miniCEOP ⫻ 6 CR: 68%
Epirubicin NA 1 (1%) grade 3–4
2012 [15] 73 years (64–84) 50 mg/m2
EFS: 46% cardiac event
No comorbidities at 5 years
OS: 63%
at 5 years
Vitolo et al., 94† Median age (range): R-megaCEOP- Epirubicin CR: 82% NA No clinical events
2009 [67] 47 years (18–60) 14 ⫻ 4 ⫹ 110 mg/m2 FFS: 73%
No major organ intensification ⫹ at 4 years
dysfunction ASCT OS: 80%
at 4 years
Zinzani et al., 51†‡ Median age (range): CIOP ⫻ 8–10 Idarubicin CR: 59% No significant 3 (11%) cardiac
1995 [68] 52 years (26–67) 10 mg/m2 PFS: 85% change events
LVEF ⬎ 50% at 30 months overall (1 moderate,
OS: 90% (⫺ 4.8%) 2 mild)
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at 42 months
Pavlovsky et al., 45†‡ Median age (range): CNOP ⫻ 6 Mitoxantrone CR: 51% NA 1 (2%) grade 4
1992 [69] 58 years (23–88) 10 mg/m2 EFS: 34% cardiac event
Normal myocardial at 4 years
function OS: 50%
at 4 years
Bezwoda et al., 161†‡ Mean age (range): CNOP ⫻ 6–8 Mitoxantrone CR: 40% ⫺ 10% or more 12 (7%) cardiac
1995 [70] 54 years (14–88) 10 mg/m2 TTF: 30% in 3 patients events; 3
Normal cardiac at 5 years (2%) early deaths
function OS: 50% for cardiac
at 5 years toxicity; 3 CHF
Burton et al., 106† Median age (range): CIOP ⫻ 6 or more Idarubicin CR: 52% NA 1 (1%) late
2005 [71] 10 mg/m 2 PFS: 40% cardiac death
49 years (25–67)
No contraindication at 4 years
to intensive therapy OS: 56%
at 4 years
76‡ CNOP ⫻ 6 ⫺ 15% or more
For personal use only.

Sonneveld et al., Median age (range): Mitoxantrone CR: 31% 2 (3%) cardiac
1995 [72] 71 years (60–84) 10 mg/m2 DFS: 13% in 9/23 deaths; 2 (3%)
LVEF ⬎ 40% at 3 years patients (39%) CHF
OS: 26%
at 3 years
Pettengell et al., 70 Median age (range): Single agent ⫻ 6 Pixantrone CR: 20% No significant 35% any grade
2012 [30] 60 years (18–80) 85 mg/m2 Mean PFS: change cardiac events
LVEF ⬎ 50%, no A 5.0 months overall
pretreatment, Mean OS: 7.5 (⫺ 4.0%)
no cardiac months ⬍ 40% in 1
abnormalities patient
Herbrecht et al., 61† Median age (range): CPOP-R ⫻ 6–8 Pixantrone CR: 75% ⫺ 10% or more 2 (3%) grade 3–4
2013 [29] 68 years (31–88) 85 mg/m2 PFS: 58% in 9 patients cardiac events
No NYHA ⬎ 2 at 3 years (15%)
OS: 69% ⫺ 20% or more
at 3 years in 1 patient
(2%)
A, anthracyclines; ASCT, autologous hematopoietic stem cell transplant; CCOP, cyclophosphamide, PLD, vincristine, prednisone; CEOP, cyclophosphamide, epirubicin,
vincristine, prednisone; CHF, congestive heart failure; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CIOP, cyclophosphamide, idarubicin, vincristine,
prednisone; CNOP, cyclophosphamide, mitoxantrone, vincristine, prednisone; CR, complete response; DFS, disease-free survival; EFS, event-free survival; FFS, failure-
free survival; LVEF, left ventricular ejection fraction; NA, not available; NHL, non-Hodgkin lymphoma; OS, overall survival; PFS, progression-free survival; R-, addition
of rituximab; TTF, time to treatment failure.
*Only the actual number of patients treated with the indicated regimen is reported.
†Untreated.
‡Intermediate or high-grade NHL.

doses of liposomal doxorubicin and conventional doxoru- a preferential distribution to liver, spleen and the lym-
bicin showed that the use of the liposomal formulation was phatic systems, and a significantly reduced risk of cardiac
associated with a significantly lower cardiac and gastroin- and mucocutaneous toxicity, makes its use particularly
testinal toxicity, with similar antitumor efficacy [84,85]. appealing for patients with NHL [87,88]. In patients with
Two liposomal formulations of doxorubicin are cur- metastatic breast cancer, the use of NPLD was shown to be
rently available: NPLD and pegylated liposomal doxorubi- associated with a reduction in cardiotoxicity and mucositis,
cin (PLD). PLD shows particular pharmacokinetic charac- while maintaining the antitumor efficacy of conventional
teristics, such as long circulation time, small distribution doxorubicin. Of note, severe hand–foot syndrome, which
volume and a safety profile considerably different from that occurs commonly with PLD, was not observed in any NPLD
of standard doxorubicin. Mucositis and skin toxicity are the recipients [21,89–91].
two major adverse events associated with PLD, while the Based on these data, the effects of substituting NPLD
risk of developing anthracycline cardiomyopathy is reduced into CHOP (COMP) have been investigated. In a phase
[86]. The pharmacokinetic and safety profile of NPLD, with 1–2 trial, the COMP regimen was shown to be effective in
 Cardiotoxicity and aggressive non-Hodgkin lymphoma 7

47 newly diagnosed patients with aggressive NHL (median The feasibility and efficacy of a biweekly dose-dense
age, 55 years), with a CR rate of 67% and an ORR of 83%, and R-COMP-14 regimen was evaluated in 41 untreated elderly
a favorable safety profile [25]. Out of 47 patients, two (4%) patients (median age, 73 years), not eligible for conventional
developed clinically silent cardiac toxicity, with both dem- anthracycline-based treatment, with poor-risk DLBCL and
onstrating a decline in LVEF of 20%. None of the patients cardiac comorbidity [27]. ORR was 73%, with 68% CR; 4-year
presented any symptoms of cardiotoxicity. disease-free survival and time to treatment failure were 72%
Subsequently, NPLD has also been incorporated into and 49%, respectively. The incidence of cardiac grade 3–4
R-CHOP (R-COMP) for the treatment of elderly patients adverse events was 17%. At mid-treatment evaluation, LVEF
and those at risk of cardiotoxicity. Between 2006 and 2008, decreased by 5–10% in eight patients, while a ⬎ 10% reduc-
a pilot study was performed to assess the safety and efficacy tion was observed in five others. With a follow-up of 1 year
of the R-COMP-21 regimen in 20 frail and elderly patients from completion of therapy, 23 of 29 surviving patients did
(median age, 73 years) with aggressive B-cell NHL [26]. not show significant differences in LVEF compared with pre-
The results were similar to those previously reported in the therapy values.
literature with the same regimen, with CR and ORR rates In a trial analyzing 35 frail elderly patients (median age,
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of 65% and 90%, respectively, but they may be considered 76 years) with previously untreated aggressive lymphoma
impressive given the high-risk and advanced-stage popula- and one or more severe comorbidities, intermediate doses of
tion studied. The cumulative percentage of cardiovascular NPLD (30 mg/m2) were used in a modified-CHOP regimen
complications was 15%, but this patient population con- ⫾ R [94]. The intention-to-treat analysis showed an ORR of
sisted solely of very old patients, with a poor World Health 86%, including 24 (69%) patients achieving CR. OS and PFS
Organization performance status and important comorbid- for all patients at 24 months were 70% and 58%, respectively.
ities. Two patients developed CHF, with a 20% decrease in As for cardiotoxicity, a decrease in LVEF was observed in five
LVEF. On the whole, the study demonstrated the feasibility patients, in two of whom CHF symptoms were also present.
of the R-COMP-21 regimen in frail and elderly patients with For the entire population, LVEF decreased slightly after che-
aggressive NHL. motherapy but not in a statistically significant manner.
A larger, prospective European multicenter study (the A direct comparison between R-COMP and R-CHOP
EUR018 trial) also investigated the efficacy of R-COMP in 72 regimens was reported in 88 patients with untreated DLBCL,
For personal use only.

elderly patients with DLBCL (median age, 72 years), 38 of randomized to receive R-CHOP or R-COMP therapy. A
whom had a history of abnormal cardiovascular conditions significantly lower mean LVEF and significantly higher
[92]. The ORR was 71%, with a CR rate of 57% in the intention- N-terminal pro-brain natriuretic peptide (NT-proBNP) level
to-treat population. After a median follow-up of 33 months, were observed at the end of treatment in the R-CHOP arm
the 3-year OS, failure-free survival and PFS rates were 72%, compared with the R-COMP arm. The remission rates were
39% and 69%, respectively. Grade 3–4 cardiac adverse events comparable in the two groups [95].
were observed in 4% [92]. Importantly, no significant reduc- Finally, NPLD was also reported to be effective in
tion in cardiac function and no change in LVEF were appar- T-cell lymphomas. Among the 37 high-risk patients with
ent during treatment. NHL (median age, 73 years), not eligible for conventional
The favorable safety profile of liposomal doxorubicin anthracycline-containing therapy, treated with the COMP
allows this treatment to be considered for patients who regimen by Heintel et al., nine were affected by T/NK-cell
might not be able to receive conventional doxorubicin neoplasms. In this subpopulation of patients, an ORR of
because of concurrent cardiac disease or pretreatment with 89% was observed, with 55% of CRs. OS analysis showed no
anthracyclines. A prospective study of R-COMP-21 therapy significant difference between these patients and those with
in this group of patients resulted in a CR rate of 76% and an DLBCL treated with R-COMP. No cardiac event in any patient
ORR of 90%, with a low incidence of cardiac events [28]. Out during or after therapy with NPLD was observed [96].
of 21 patients, only one case of CHF was observed (4.7%). On the whole, these results show that regimens containing
Among the 15 patients who were followed up for at least liposomal doxorubicin are feasible and effective in patients
12 months after the end of therapy, none presented any with poor-risk aggressive lymphoma who would have been
cardiac dysfunction or significant decrease in LVEF. denied anthracycline-based treatment owing to age and/or
Results of a study of 80 elderly patients (mean age, 70.9 cardiac morbidity. When substituted for conventional doxo-
years) with poor-risk DLBCL treated with R-COMP-21 were rubicin in a CHOP or R-CHOP regimen, NPLD resulted in
recently reported by Dell’Olio et al. [93]. The ORR was 96.2%, comparable clinical efficacy, with a favorable safety profile.
with 82.5% of patients showing a CR. The estimated probabil- Many of these patients eventually achieved complete and
ity of OS at 12 and 24 months from admission was 93.5% and durable responses, confirming the value of intensive therapy
87.3%, respectively, with 77.5% of patients alive and disease- also in this category of patients. Of note, some authors also
free after a median follow-up of 31 months. There were no demonstrated that, at variance with conventional doxorubi-
therapy-related cardiac events and the ejection fraction cin, NPLD-based regimens may be equally effective in both
improved (from 51.6 ⫾ 6.9% to 54.2 ⫾ 3.9%), although the MDR1-positive and MDR1-negative cases [25], probably
change was not statistically significant. Eighteen patients had because of the ability of NPLD to overcome excessive drug
an impaired cardiac function at baseline, with LVEF ⬍ 50%, efflux due to p-glycoprotein (MDR1) overexpression [95].
which increased from a mean baseline value of 42.3% to PLD has demonstrated a high antitumor activity and favor-
50.4% at last observation. able safety profile in patients with breast and ovarian cancer,
 8 P. L. Zinzani et al.

acquired immune deficiency syndrome (AIDS)-associated patients with NHL aged ⱖ 65 years have a high prevalence
Kaposi sarcoma and multiple myeloma (in association of diabetes (32%), hypercholesterolemia (54%) and hyper-
with bortezomib), and it is registered in Europe for these tension (73%) [103], all recognized risk factors for CHF in
indications. Its distinctive pharmacokinetic features make the general population [104]. The interaction of doxorubicin,
the drug very active in cutaneous T-cell lymphoma [97]. cardiac risk factors and cardiac toxicity in elderly patients
However, a number of trials have also investigated the effi- with DLBCL was analyzed by Hershman et al. in a population
cacy of PLD in aggressive NHL [98–100], following the first of 9438 patients aged ⱖ 65 years receiving doxorubicin-based
evidence of efficacy and reduced cardiotoxicity in patients chemotherapy [105]. On the whole, doxorubicin increased
with DLBCL treated with the CHOP-Bleo regimen, using the risk of subsequent cardiotoxicity, with a hazard ratio of
PLD instead of doxorubicin [101]. In 33 untreated elderly 1.29. Hypertension was the only cardiac risk factor to act
patients with DLBCL (median age, 74 years), 6–8 cycles of synergistically with doxorubicin, intensifying the effect of the
the CCOP regimen (cyclophosphamide, PLD, vincristine, drug on the risk of CHF (hazard ratio, 1.8).
prednisone) resulted in an ORR of 64% and a 1-year PFS Alongside elderly people, it is also important to identify
of 64%, without clinical cardiac events [100]. Adding R, cardiac risk factors in younger patients treated with anthracy-
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an ORR and a CR rate of 76% and 59%, respectively, were cline-based regimens, as they may increase the susceptibility
obtained in a population of 30 elderly untreated patients of younger patients to anthracycline-associated cardiotoxic-
with DLBCL (median age: 69 years) receiving a modified ity [106], underlining the importance of a detailed clinical
R-CHOP regimen, including PLD 30 mg/m2 in replacement examination also in apparently healthy young people. A
of conventional doxorubicin [102]. The projected 2-year family history of CHF and coronary artery disease has been
EFS and OS were 65.5% and 68.5%. LVEF evaluation and shown to increase the long-term cardiovascular risk in sur-
troponin levels did not show significant changes over the viving patients with Hodgkin lymphoma, irrespective of age
course of treatment. A single episode of arrhythmia was [107], suggesting the importance of this factor for identifying
registered in a patient with a previous history of atrial fibril- patients at cardiac risk.
lation. Based on this favorable safety profile, the R-CCOP To date, we do not have definitive tests to exactly predict
regimen was assessed in a trial performed in 21 elderly the risk of cardiotoxicity in patients receiving anthracycline
patients with NHL with high cardiac risk (median age, therapy, and an extensive monitoring program is gener-
For personal use only.

72 years), resulting in an ORR of 85% and 2-year EFS of ally used in clinical practice with the intent of defining the
58%. Median LVEF did not change after treatment compared “cardio-oncologic risk” of patients. On the basis of demo-
with baseline, and one acute cardiac death was recorded graphic and clinical characteristics of the patients and of
in this population with pre-existing cardiac dysfunction. the prescribed treatment (including risk factors, prior car-
However, 25% of patients developed a hand–foot syndrome diac diseases, and drug and schedule used), the probability
leading to discontinuation of treatment, in association with of cardiac adverse events may be assessed [103,108]. This
weekly doses of PLD exceeding 15 mg/m2, prompting the risk must always be balanced against the potential benefits
authors to caution against surpassing this dose [99]. of treatment, and the final decision might be different in
The efficacy and toxicity of liposomal doxorubicin-based different clinical settings.
regimens in aggressive NHL are summarized in Table III. The current clinical practice for the screening of eligibility
to anthracycline-based regimens is primarily based on the
assessment of LVEF by transthoracic echocardiography or
How to identify patients with high-risk disease
radionuclide angiocardiography, but more recent advances in
As the use of anthracyclines, both standard and in the lipo- molecular imaging using cardiac magnetic resonance imag-
somal formulation, is still crucial for improving survival ing might allow a more precise detection of patients at high
outcomes in patients with aggressive lymphomas, there is a risk [109]. With major widespread use of these techniques,
strong need to precisely identify patients at high risk of car- the current reliance on LVEF to determine which patients
diotoxicity, so as to assess the risk–benefit balance in each are at high risk for developing cardiomyopathy might be
patient and evaluate the individual probability of lifetime re-evaluated. Screening tests should be done before begin-
incidence of anthracycline cardiotoxicity against the poten- ning therapy and at appropriate points based on baseline
tial benefits of therapy. results, therapy scheme and the patient’s clinical status. As
It is generally acknowledged that age is the most impor- discussed below, serum biomarkers such as NT-proBNP and
tant risk factor for chemotherapy-associated toxicity. How- cardiac troponin have also been assessed as possible means
ever, although the elderly account for the majority of patients of early detection of cardiac risk, but their role as a screening
with cancer, they are generally under-represented in major tool remains to be established.
clinical trials, and our knowledge about the potential benefits As a practical approach, the European Society for Medical
and risks of cytotoxic therapies is sparse in this population Oncology (ESMO) clinical practice guidelines recommend
of patients. Age represents a risk factor for anthracycline- that the cardiovascular evaluation of patients before treat-
associated cardiotoxicity independent from other factors ment with anthracyclines includes, besides a careful clinical
[7], yet elderly patients are more likely to have comorbidities evaluation and assessment of cardiovascular risk factors or
and risk factors that may increase the likelihood of cardiac comorbidities, electrocardiogram (ECG) and clinical car-
adverse events. Data from the Surveillance, Epidemiology, diovascular evaluation to screen for signs of cardiomyopa-
and End Results (SEER)-Medicare database showed that thy, conduction disturbances and QT interval. LV fractional
 Cardiotoxicity and aggressive non-Hodgkin lymphoma 9

Table III. Liposomal doxorubicin-based regimens in aggressive non-Hodgkin lymphoma*.

Patients Reasons for LD
Reference (n) choice Treatment Drug Outcome LVEF post-treatment Cardiac events
Visani et al., 20 Median age (range): R-COMP ⫻ 4–6 NPLD 50 mg/m2 CR: 65% No change in 17/20 2 cases of CHF;
2008 [26] 73 years (61–82) DFS: 83% patients; ⫺ 20% in 1 case of fatal
Hypertension: 50% at 2 years 2 patients (10%) pulmonary
Cardiac OS: 90% at 2 years embolism
comorbidities§:
80%
Pretreated: 15/20
(75%)
Luminari et al., 72† Median age (range): R-COMP ⫻ 8 NPLD 50 mg/m2 CR: 57% No change overall; 4% grade 3–4
2010 [92] 72 years (61–83) PFS: 69% ⫺ 20% or cardiac events;
Hypertension: 39% at 3 years drop ⬍ 50% in 1 case of fatal
Cardiac OS: 72% at 3 years 4/72 patients (5%) CHF
comorbidities§:
53%
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Rigacci et al., 21 Median age (range): R-COMP ⫻ 4–6 NPLD 50 mg/m2 CR: 76% No change in 20/21 1 case of CHF
2007 [28] 70 years (54–76) DFS: 78% at 1 year patients; ⫺ 30% in
Hypertension: 29% OS: 76% 1 patient (5%)
Cardiac at 19 months
comorbidities§:
62%
Pretreated: 38%
(median dose of
D: 518 mg/m2)
Dell’Olio et al., 80† Median age (range): R-COMP ⫻ 6–8 NPLD 50 mg/m2 CR: 82.5% No change overall No clinical events
2011 [93] 71 years (54–83) PFS: 86%
Hypertension: 9% at 2 years?
Cardiac OS: 87% at 2 years
comorbidities§:
47%
Corazzelli 41† Median age (range): R-COMP-14 ⫻ 6 NPLD 50 mg/m2 CR: 68% No change overall; 17% grade 3–4
For personal use only.

et al., 2011 73 years (62–82) TTF: 49% ⬍ 40% in 3/41 cardiac events
[27] Hypertension: 29% at 4 years patients (7%)
Cardiac OS: 67% at 4 years
comorbidities§:
100%
Gimeno et al., 35† Median age (range): R-CMyOP ⫻ 4–6 NPLD 30 mg/m2 CR: 69% No change overall; 14% cardiac
2011 [94] 76 years (61–88) PFS: 58% ⬍ 50% in 4/35 events; 2 cases
Hypertension: 63% at 2 years patients (11%) of CHF
Cardiac OS: 70% at 2 years
comorbidities§:
87%
Martino et al., 33† Median age (range): CCOP (CHOP PLD 30 mg/m2 CR: 49% No change overall No clinical events
2002 [100] 74 years (61–83) with PLD) PFS: 64% at 1 year
⫻ 6–8 OS: 55% at 1 year
Zaja et al., 30† Median age (range): R-CHOP (with PLD 30 mg/m2 CR: 59% No change overall 1 episode of
2006 [102] 69 years (60-75) PLD) ⫻ 6 EFS: 65.5% at 2 arrhythmia
No previous history years
of cardiac disease OS: 68.5% at 2
years
Schmitt et al., 21‡ Median age: 72 R-CHOP (with PLD 30 mg/m2 CR: 40% No change overall 1 acute cardiac
2012 [99] years PLD) ⫻ 6 EFS: 58% at 2 death
Elderly and/or years
cardiac risk OS: 58% at 2 years
CHF, congestive heart failure; COMP, cyclophosphamide, NPLD, vincristine, prednisone; CR, complete response; DFS, disease-free survival; NA, not available; NHL,
non-Hodgkin lymphoma; NPLD, non-pegylated liposomal doxorubicin; OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; EFS,
event-free survival; R-, addition of rituximab.
*If not specified, CCOP, R-COMP and R-CMyOP every 3 weeks. Only the actual number of patients treated with the indicated regimen is reported.
†Untreated.
‡Intermediate or high-grade NHL.
§Diabetes, coronary heart disease, myocardiopathy, arrhythmias, valvulopathy.

shortening and LVEF are indicated as the most useful indices assess for cardiovascular evaluation before anticancer treat-
for assessment of cardiac function. With respect to imaging ment with cardiotoxic drugs [111].
techniques, the baseline echocardiogram remains the stan- A different approach is required for patients with previ-
dard approach to assess cardiac function. Magnetic reso- ous cardiovascular disease. In these patients cardiologic
nance imaging can be used to assess myocardial function, to screening will require particular attention, and the imple-
evaluate myocardial perfusion and for tissue characteriza- mentation of measures aimed at reducing the cardiotoxic-
tion, and may have potential in the future [110]. The recently ity of anthracyclines must be considered. These measures
published new version of the guidelines provides a detailed may include dose and follow-up adjustments, and the use
account of the echocardiographic and clinical parameters to of cardioprotectants or liposomal anthracyclines [111], but
 10 P. L. Zinzani et al.

precise risk–benefit guidelines for these patient subgroups and the clinician would need to extrapolate data on dif-
still need to be established. ferent agents to assess the global risk of cardiac toxicity.
The cardiotoxicity of anthracyclines may manifest years
or even decades after treatment, a possibility that physi-
How to limit cardiotoxicity
cians should keep in mind during the long-term follow-up
Early detection of cardiac injury is crucial in patients of patients. In the ESMO guidelines the assessment of
receiving anthracycline-based regimens, because it may cardiac function is recommended 4 and 10 years after
facilitate early therapeutic measures and avoid the decline anthracycline therapy in children (⬍ 15 years of age) or
into heart failure. in those who received a cumulative dose of doxorubicin
Endomyocardial biopsy represents the most reliable ⬎ 240 mg/m2 [111], but regular cardiac monitoring may
method for evaluating myocardial damage, but because of be advisable, at the physician’s discretion, in special
specific technical limitations its feasibility in daily clinical subgroups of patients, such as those with hypertension,
practice for cardiotoxicity monitoring is limited. diabetes or coronary artery disease.
The echocardiographic evaluation of LVEF is thus The purpose of regular cardiac monitoring is early
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recommended by ESMO even in asymptomatic patients detection and prompt management of incipient heart
at baseline, and 3, 6 and 9 months during treatment, and failure. Although no specific indications are given for
then at 12 and 18 months after the initiation of therapy with different subgroups of patients, an LVEF decline to ⬍ 50%
anthracycline. Increased vigilance is recommended for may be a cut-off value for reassessment and further cardiac
patients ⱖ 60 years of age [111]. However, LVEF is not able checks. In case of LVEF decline to ⬍ 40%, chemotherapy
to detect subtle changes in myocardial function, and severe withdrawal is indicated [111]. The early management of LV
heart damage can be sustained before it becomes evident in dysfunction, even if asymptomatic, is mandatory to prevent
measurable reductions in LVEF [112,113]. It is now recog- the decline of cardiac function into CHF. It has been shown
nized that the Doppler-derived diastolic indices represent that the time elapsed from the end of chemotherapy to the
an early indication of LV dysfunction in patients with cancer, start of heart failure therapy (time to treatment) is a crucial
so that detection of diastolic changes of LV function before variable for recovery of cardiac dysfunction, as the likeli-
systolic dysfunction occurs may represent the earliest sub- hood of obtaining a complete LVEF recovery is higher in
For personal use only.

clinical sign of cardiotoxicity [114]. patients in whom treatment is initiated within 2 months of
Serum biomarkers may potentially represent another test the end of chemotherapy [78,118]. ACE inhibitors and beta
for the identification and monitoring of cardiotoxicity after blockers should then be administered as early as possible
anthracycline administration, and certain studies have sug- to ensure a better probability of a therapeutic response
gested their usefulness in this setting. NT-proBNP is a cardiac [103,110]. It must be stressed that the purpose of treatment
hormone released by the myocardium in response to volume may also be to allow patients to complete their antineoplas-
overload, and high levels of BNP have been reported to cor- tic therapy.
relate with LV dysfunction in patients with cancer treated In elderly people, rigorous screening and careful moni-
with oncologic therapy [115]. In an analysis of 703 patients toring of cardiac function is even more critical, not only to
with cancer, the troponin I release pattern after high-dose avoid an excessive life-threatening risk of toxicity but also
chemotherapy was able to identify patients at different risks to ensure that fit patients who are able to withstand the
of cardiac events in the following 3 years [116]. However, toxic effects of therapy are not excluded from a potentially
other studies failed to find any advantage from biomarker curative treatment. Close monitoring of cardiac function
assessment over the monitoring of LVEF [117], and further every 2–3 cycles of conventional anthracycline administra-
evidence is required to confirm the sensitivity and the speci- tion, with special attention paid to an LVEF drop of ⬎ 10%,
ficity of these parameters. The new ESMO guidelines, while even if within the normal range, appears to be a cautious
stating that the usefulness of routine monitoring of serum procedure for patients aged 70 years and older [103,119].
biomarkers is still to be definitely established, recommend Particularly in elderly patients with hypertension, diabetes
the assessment of troponin I or BNP concentrations at or coronary artery disease, measures to prevent cardiac tox-
baseline and periodic measurements during anthracycline icity (such as prolonged infusion, cardioprotectants or use
therapy (each cycle) to identify patients who need further of liposomal formulations) may be considered, while the
cardiac assessment [111]. development of cardiotoxicity requires an aggressive treat-
A careful basal clinical examination and close moni- ment with ACE inhibitors, angiotensin receptor blockers,
toring is of utter importance for patients previously beta blockers and diuretics when there are documented
exposed to anthracycline therapy or close to the limiting signs of congestion [103].
cumulative dose. The limits are well defined for doxoru-
bicin (⬎ 500 mg/m2), and for some of the most used drugs
Conclusion and future developments
(epirubicin ⬎ 720 mg/m2; mitoxantrone ⬎ 120 mg/m2),
but less evidence exists for new drugs and liposomal For patients with aggressive NHL, anthracycline-based
doxorubicin. For NPLD the maximum cumulative dose is regimens remain the treatment of choice. However, despite
defined as 1260 mg/m2. Even more difficult is the man- the remarkable advances in methods for early detection
aging of cumulative doses when several anthracyclines of heart failure and evidence-based guidelines to treat it,
are employed. No guidelines are available on this matter, cardiotoxicity may still hamper the delivery of optimal
 Cardiotoxicity and aggressive non-Hodgkin lymphoma 11

doses of chemotherapy and represent a life-threatening [2] Visani G, Isidori A . Nonpegylated liposomal doxorubicin in
the treatment of B-cell non-Hodgkin’s lymphoma:where we stand.
complication.
Expert Rev Anticancer Ther 2009;9:357–363.
Two factors have increased this problem in recent [3] Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy
years: the progressive improvement in the life expectancy plus rituximab compared with CHOP alone in elderly patients with
diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242.
of patients with aggressive lymphomas, including elderly
[4] Pfreundschuh M, Trumper L, Osterborg A , et al. CHOP-like
patients, and the rising number of older people in the gen- chemotherapy plus rituximab versus CHOP-like chemotherapy alone
eral population. As more patients are receiving more than in young patients with good-prognosis diffuse large-B-cell lymphoma:
a randomised controlled trial by the MabThera International Trial
one line of treatment, the cumulative cardiotoxicity of these
(MInT) Group. Lancet Oncol 2006;7:379–391.
drugs may become a limitation and preclude the adminis- [5] Gianni L, Herman EH, Lipshultz SE, et al. Anthracycline
tration of the most effective therapy. Elderly patients, who cardiotoxicity: from bench to bedside. J Clin Oncol 2008;26:3777–3784.
[6] Johnson SA . Anthracycline-induced cardiotoxicity in adult
today account for most patients with lymphoma and whose
hematologic malignancies. Semin Oncol 2006;33: S22–S27.
number is steadily growing, are often refused anthracycline [7] Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients
therapy because of concerns about cardiotoxicity. However, treated with doxorubicin: a retrospective analysis of three trials. Cancer
2003;97:2869–2879.
the prognosis of older patients may be as good as that of
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[8] Von Hoff DD, Layard MW, Basa P, et al. Risk factors for
younger ones if adequate intensive chemotherapy regi- doxorubicin-induced congestive heart failure. Ann Intern Med 1979;
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[9] Fields PA , Linch DC. Treatment of the elderly patient with diffuse
clinical practice.
large B cell lymphoma. Br J Haematol 2012;157:159–170.
A better definition of patients at high risk, taking into [10] van de Schans SA , Issa DE, Visser O, et al. Diverging trends in
account not only age but also comorbidities, general fitness incidence and mortality, and improved survival of non-Hodgkin’s
lymphoma, in the Netherlands, 1989-2007. Ann Oncol 2012;23:
and evidence-based assessment of individual risk–benefit
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Writing support was funded by Teva. Teva had no role in devel- and preserved antitumor efficacy of liposome-encapsulated
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Potential conflict of interest: Disclosure forms provided
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