Cardiotoxicity by Chemotherapeutic agents simplified.

1. CHEMOTHERAPY
INDUCED
CARDIOTOXICITY
Dr. VISHAL VANANI
Jaslok Hospital, Mumbai

2. • Cancer patients who are undergoing chemotherapy have an
increased risk of developing cardiovascular complications, and
the risk is even greater if there is a known history of heart
disease.
• Among the serious clinical cardiac complications that have been
reported are
 Arrhythmias
 Myocardial necrosis causing a dilated cardiomyopathy
 Vasoocclusion or vasospasm resulting in angina or myocardial
infarction

3. • A wide range of chemotherapy agents have been associated
with cardiotoxicity.
• The anthracyclines and related compounds (doxorubicin,
daunorubicin, idarubicin, epirubicin, and the anthraquinone
mitoxantrone) are some of the most frequently implicated
agents*
*Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;

4. CARDIOTOXIC CHEMOTHERAPY
• Interleukins
• Interferons
• Anthracyclines
• Antimetabolites
• Antimicrotubules
• Monoclonal Antibodies
• Tyrosine kinase inhibitors
• Alkylating agents
• Arsenical Compounds

6. • One of the most common manifestations of cardiotoxicity
associated with exposure to anticancer therapies is the
development of LVD and overt heart failure (HF).
• The definition of LVD proposed by the Cardiac Review and
Evaluation Committee supervising Trastuzumab clinical
trials* is
1. Decrease in cardiac LV ejection fraction (LVEF) that was either
global or more severe in the septum;
2. Decline in LVEF of at least 5% to less than 55% with
accompanying signs or symptoms of CHF, or
3. Decline in LVEF of at least 10% to below 55% without
accompanying signs or symptoms.
*National Cancer Institute. Cancer therapy evaluation program. [on-line]
http ://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ ctcv20_4e30e992.pdf

7. NONREVERSIBLE DAMAGE AND
REVERSIBLE DYSFUNCTION
• Types of Cardiotoxicity :
• Type I cardiotoxicity
• The pathophysiology is related to cell loss
• Type II cardiotoxicity
• Cellular dysfunction (mitochondrial and protein alterations).
• While non reversible damage can induce progressive CV
disease, a reversible dysfunction is usually temporary, with no
injury marker release and will be recovered with
normalization of CV function.

8. ANTHRACYCLINES
• In the initial trials of doxorubicin and daunorubicin, chemotherapy-
induced myelosuppression was usually a dose- limiting factor,
thereby preventing the administration of sufficiently high doses to
cause cardiotoxicity.
• With the emergence of more intensive regimens and better
supportive care, cardiomyopathy and heart failure were recognized
as complications of prolonged treatment.
• The development of noninvasive monitoring techniques allowed the
recognition of subclinical toxicity in a much larger number of
patients exposed to anthracyclines.

9. ANTHRACYCLINES:
BACKGROUND
• Purpose: anti-cancer, chemotherapy
• Ca breast, soft tissue sarcoma, leukemia, lymphoma, childhood
tumors
• Therapeutic mechanism:
• insertion into DNA of replicating cells, → DNA fragmentation,
decreased DNA, RNA and protein synthesis
• Toxicity via: free radicals*, ↑ oxidative stress
• Loss of myofibrils and the vacuolization of cytoplasm
• Examples: doxorubicin (Adriamycin®), daunorubicin
(Cerubidine®), epirubicin (Pharmorubicin®), mitoxantrone
(Novantrone® [anthracendione])
*Myers C. Role of iron in anthracycline action. In: Hacker M, Lazo J, Tritton T, eds. Organ Directed Toxicities of Anticancer
Drugs. Boston, Mass: Martinus Nijhoff; 1988:17–30

10. ANTHRACYCLINES AND HEART
• Acute cardiotoxicity (<1%)
• occurs in immediately after infusion of the anthracycline
• manifests as an acute, transient decline in myocardial contractility,
which is usually reversible
• Early-onset chronic progressive cardiotoxicity (1.6 – 2.1%)
• during therapy or within the first year after treatment
• dilated CMP in adults, which can be progressive
• Late- onset chronic progressive cardiotoxicity (1.6 – 5%)
• occurs at least 1 year after completion of therapy
• dilated CMP in adults, which can be progressive
• may not become clinically evident until 10–20 years after the first
dose of cancer treatment

11. ACUTE TOXICITY
• Acute cardiotoxicity may present as
 Nonspecific ST-segment and T-wave abnormalities,
 Arrhythmias (both supraventricular and ventricular),
 Heart block (including Mobitz type II second degree AV
block and complete heart block),
 Ventricular dysfunction,
 an increase in plasma brain natriuretic peptide, or
 pericarditis-myocarditis syndrome (particularly with
mitoxantrone)
Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996; 125:47
Steinberg JS, Cohen AJ, Wasserman AG, et al. Acute arrhythmogenicity of doxorubicin administration. Cancer 1987; 60:1213
Doroshow JH. Doxorubicin-induced cardiac toxicity. N Engl J Med 1991; 324:843

12. • Most of these events are not life-threatening and they resolve
in a week
• Some studies suggest that acute myocardial injury can be
used to predict the future development and severity of
ventricular dysfunction.*
• However, the relationship between acute toxicity and the
subsequent development of chronic cardiotoxicity is unclear.
*Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose
chemotherapy. J Am Coll Cardiol 2000; 36:517

13. CHRONIC TOXICITY
• Regardless of its timing, chronic cardiomyopathy generally
begins as asymptomatic diastolic or systolic dysfunction, and
progresses to heart failure, which may be fatal.
• The incidence of chronic cardiotoxicity is most closely related
to the cumulative dose of anthracycline administered.
• The prevalence of cardiomyopathy increases significantly
when patients are given doses of doxorubicin >550 mg/m2.

14. ANTHRACYCLINES: INCIDENCE
Cumulative Dose Heart Failure
~400 mg/m2 3 - 5%
~550 mg/m2 7 - 26%
~700 mg/m2 18 - 48%
Von Hoff et al, Ann Intern Med 1979
• Studies evaluating cumulative probability of doxorubicin-induced
HF
• The recommended maximum lifetime cumulative dose for
doxorubicin is 400–550 mg/m2

15. ANTHRACYCLINES:
MAXIMUM “SAFE” DOSES
Drug Dose
doxorubicin 550 mg/m2
danorubicin 600 mg/m2
epirubicin 1000 mg/m2
idarubicin 100 mg/m2
Mitoxantrone 160 mg/m2

16. RISK FACTORS FOR
ANTHRACYCLINE TOXICITY
• age (young and elderly)
• female gender
• higher single doses
• cumulative dose
• increased length of time
since completion of
chemotherapy
• intravenous bolus
administration
• history of prior irradiation
• underlying CV disease
• increase in cardiac biomarkers
troponins and natriuretic
peptides, during and after
administration
Cardinale D, Sandri MT, Colombo A et al. Prognostic value of Troponin I in cardiac risk stratification of cancer patients
undergoing high-dose chemotherapy. Circulation. 2004; 109: 2749–2754
Braverman AC, Antin JH, Plappert MT et al. Cyclophosphamide cardiotoxicity in bone marrow transplantation: a
prospective evaluation of new dosing regimens. J Clin Oncol. 1991; 9: 1215–1223
• the use of other concomitant agents known to have
cardiotoxicity including cyclophosphamide, transtuzumab and
paclitaxel

17. MONITORING
• Normal EF
• Baseline (prior to 100 mg/m2)
• 2nd study after 250 to 300 mg/m2
• 3rd at 400-450 mg/m2
• Sequential studies prior to each additional dose
• EF 30-50%
• EF study prior to each dose
• EF < 30% - recommend against initiating

18. • On monitoring,
• If LVEF has decreased by either 15 percentage-points, or 10
percentage-points to a value below 50 and a repeat assessment
after 3 weeks confirms the finding or
• if troponin or BNP are elevated
alternative chemotherapeutic options should be discussed,
as continuing treatment with an anthracycline carries
increased risk for cardiotoxicity
• Discontinue doxorubicin for decrease in EF >15% or absolute
< 30%

20. ANTHRACYCLINES:PREVENTION
• Altering infusion protocol
• Alternate anthracycline derivatives
• Liposomal preparations
• Dexrazoxane - metal-chelating agent
• Beta-blockers
• ACE inhibitors

21. ALKYLATING AGENTS
• LVD has been associated with cyclophosphamide therapy in
7% – 28% of patients. In addition, there are, as well, reports of
hemorrhagic pericardial effusions and myopericarditis.
• The risk of cardiotoxicity appears to be dose related
• (≥150 mg/kg and 1.5 g/m2/day).
• Total dose of individual course rather than cumulative dose.
Goldberg MA, Antin JH, Guinan EC et al. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood. 1986; 68: 1114–1118.
Quezado ZM, Wilson WH, Cunnion RE et al. High-dose ifosfamide is associated with severe, reversible cardiac dysfunction. Ann Intern Med.
1993; 118: 31–36.

22. ALKYLATING AGENTS
• Another alkylating agent, ifosfamide, can induce arrhythmia
and onset of HF, with a dose–response trend (doses ≥12.5 g/
m2).
• Busulfan is asociated with pericardial and endomyocardial
fibrosis at cumulative doses of >600 mg.

23. ALKYLATING AGENTS
• Cisplatin
• Acute clinical syndrome: chest pain, palpitations, and,
occasionally, elevated cardiac enzymes indicative of myocardial
infarction (MI).
• Late cardiovascular complications: hypertension, LV
hypertrophy, myocardial ischemia, and MI (as long as 10 to 20
years after the remission of metastatic testicular cancer)
• Nephrotoxicity, experienced by up to 35% of patients receiving
cisplatin, can lead to significant hypomagnesemia and
hypokalemia, which in turn can cause cardiac arrhythmias.
Berliner S, Rahima M, Sidi Y, et al. Acute coronary events following cisplatin-based chemotherapy.
Cancer Invest. 1990;8:583–586

24. INHIBITORS OF MICROTUBULE
POLYMERIZATION
• Paclitaxel and docetaxel are widely used in the treatment of multiple
malignancies.
• The incidence of HF : relatively low.
• In the Breast Cancer International Research Group trial, the overall
incidence of CHF (including that during follow-up) was 1.6% among
patients treated with docetaxel–doxorubicin– cyclophosphamide
Slamon D, Eiermann W, Robert N et al. Adjuvant trastuzumab in HER2-positive breast cancer.
N Engl J Med. 2011; 365(14): 1273–1283

25. INHIBITORS OF MICROTUBULE
POLYMERIZATION
• Paclitaxel has been reported to cause sinus bradycardia, heart
block, premature ventricular contractions, and ventricular
tachycardia*.
• In a large study of approximately 1000 patients, the incidence of
cardiac toxicity was 14%, and most incidents (76%) were
asymptomatic bradycardia^.
• Vinca alkaloids have been reported to cause autonomic
neuropathy, angina with ECG changes, and myocardial ischemia
and MI.
• The occasional clinical presentation of Prinzmetal’s angina and
reversible ECG changes has led to the hypothesis of ischemia
induced by coronary spasm.
*Rowinsky EK, McGuire WP, Guarnieri T, et al. Cardiac disturbances during the administration of Taxol. J Clin Oncol. 1991;9:1704–1712
^Trimble EL, Adams JD, Vena D, et al. Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to
National Cancer Institute Treatment Referral Center 9103. J Clin Oncol. 1993;11:2405–2410

26. TYPE II AGENTS
• Monoclonal antibodies and targeted agents not associated
with cumulative dose-related cardiotoxicity: type II agents
• Monoclonal antibodies
• Transtuzumab
• Bevacizumab
• Tyrisine kinase inhibitors
• Imatinib
• Lapatinib
• Sunitinib

27. TRASTUZUMAB
• Rates of cardiac toxicity reported in the adjuvant trials of
trastuzumab have been variable.
• Aysmptomatic LV dysfunction: 4-17%
• Symptomatic CHF: up to 4.5%
• Mechanism unknown, but may include:
• Interaction with other chemotherapeutic agents
• Antibody-dependent cell-mediated cytotoxicity
• Downregulation/inhibition of ERBB2 signalling

28. TRASTUZUMAB
• The risk factors for trastuzumab-associated cardiotoxicity
identified from clinical trials are:
• prior treatment with anthracycline chemotherapy
• a borderline LLN LVEF
• prior treatment with antihypertensive medication
• older age
• a poorly understood result found in one trial, a body mass index >25
kg/m2
• In all adjuvant clinical trials, a common finding was that cardiac
dysfunction and HF occurred predominantly during the
trastuzumab treatment and was frequently reversible.

29. BEVACIZUMAB
• Bevacizumab, a humanized monoclonal antibody directed against
vascular endothelial growth factor (VEGF)
• Newly developed or worsening hypertension is a commonly observed
side effect.
• In clinical trials, severe hypertension occurred in up to 5% of
patients, with rare cases of hypertensive crises of encephalopathy
and subarachnoid haemorrhage.
Perez EA, Koehler M, Byrne J et al. Cardiac safety of lapatinib: pooled analysis of 3689
patients enrolled in clinical trials. Mayo Clin Proc. 2008; 83: 679–686

30. TYROSINE KINASE INHIBITORS
• Purpose: anti-cancer, chemotherapy
• hematologic cancers, breast cancer, gastrointestinal stromal
tumor (GIST)
• Therapeutic Mechanism: inhibition of dysregulated TKs
causal/contributory to tumorigenesis
• Humanized monoclonal antibodies
• Small-molecule TKIs
• Cardiotoxicity: asymptomatic LV dysfunction, CHF
• Examples: Lapatinib, sunitinib (Sutent®), imatinib (Gleevec®,
Glivec®)

31. SUNITINIB
• Experience to date in a relatively small studied population
suggests relatively low rates of symptomatic cardiac failure
(1.4%), specifically in a population with prior exposure to
anthracycline and trastuzumab.
• Initial reports of sunitinib in renal cell carcinoma suggested a
10% incidence of asymptomatic drop in LVEF to >10% LLN,
with full recovery when treatment was completed.
Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell
carcinoma. N Engl J Med. 2007; 356: 115–124.

32. ANTIMETABOLITES
• 5-fluorouracil (5-FU): The most commonly described cardiotoxic effect
is the ischemic syndrome, which varies clinically from angina
pectoris to acute MI.
• A “rechallenge” with 5-FU frequently reproduces the clinical
cardiotoxicity. The ischemia is usually reversible on cessation of the
5-FU and implementation of anti-ischemic medical therapy.
• Ischemia can occur in patients without underlying coronary artery
disease (CAD) (incidence, 1.1%), but the incidence is higher in
patients with CAD (4.5%).
Gradishar WJ, Vokes EE. 5-Fluorouracil cardiotoxicity: a critical review. Ann Oncol. 1990;1:409–414

33. ANTIMETABOLITES
• Capecitabine is currently used in the treatment of breast and
gastrointestinal cancers and is believed to be less toxic than 5-
FU.
• Other reported cardiotoxic effects associated with capecitabine
include angina or MI, arrhythmias, ECG changes, and
cardiomyopathy

34. TYPE II AGENTS
• Optimal surveillance for patients treated with Type II agents is not
well established.
• Patients who have received both anthracyclines and anti-HER2
agents who develop cardiac failure should be treated and monitored
as patients with an irreversible cardiac toxicity.
• Those who develop cardiac dysfunction during or following treatment
with type II agents in the absence of anthracyclines can be observed
if they remain asymptomatic and LVEF remains ≥40%.
• Persistently low or further declines in LVEF or development of
symptoms should trigger discussion of risk and benefit with the
treating oncologist, as well as consideration for pharmacologic
cardiac treatment.

35. INTERLEUKINS
• High-dose IL-2 treatment results in adverse cardiovascular and
hemodynamic effects similar to septic shock and can lead to
hypotension, vascular leak syndrome, and respiratory
insufficiency requiring pressors and mechanical ventilation
support.
• Severe cases may result in cardiac arrhythmias, MI,
cardiomyopathy, and myocarditis.
• Slowing or terminating the infusion and administering
antihistamines, steroids, and epinephrine can relieve these
reactions.
• Premedication with steroids can also prevent or ameliorate acute
infusion events.
White RL Jr, Schwartzentruber DJ, Guleria A, et al. Cardiopulmonary toxicity of treatment with high dose interleukin-2 in
199 consecutive patients with metastatic melanoma or renal cell carcinoma. Cancer. 1994;74:3212–3222

36. INTERFERONS
• Interferons usually cause acute symptoms during the first 2 to
8 hours after treatment, including flu-like symptoms,
hypotension or hypertension, tachycardia, and nausea and
vomiting.
• In severe cases, angina and MI have been reported.
Vial T, Descotes J. Immune-mediated side-effects of cytokines in humans.
Toxicology. 1995;105:31–57

37. ARSENIC TRIOXIDE
• Arsenic is commonly known to cause ECG abnormalities, producing
QT prolongation in >50% of patients.
• Other side effects include sinus tachycardia, nonspecific ST-T
changes, and torsades de pointes.
• In one study, the most common acute side effect was fluid retention
with pleural and pericardial effusions.
• In addition to prolonged QT interval, complete heart block and
sudden death have also been reported.
• In these cases, the infusion of arsenic had been completed 7 to 22
hours before the event, underscoring the importance of continuous
monitoring after the infusion has been completed.
Soignet SL. Clinical experience of arsenic trioxide in relapsed acute promyelocytic leukemia.
Oncologist. 2001;6(suppl 2):11–16

38. EARLY DETECTION OF
ANTICANCER DRUG-INDUCED
LVD
• At present, the most frequently used modality for detecting
cardiotoxicity is the periodic measurement of LVEF by using either
echocardiography or multigated acquisition scanning.
• To date, however, there are no evidence based guidelines for
cardiotoxicity monitoring during and after anticancer therapies.
• Although several guidelines are available, none specify how often, by
what means, or how long cardiac function should be monitored
during and after cancer treatment*.
*Eschenhagen T, Force T, Ewer M et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart
Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2011; 13: 1–10

39. • LVEF measurement is a relatively insensitive tool for
detecting cardiotoxicity at an early stage.
• This is largely because no considerable change in LVEF occurs
until a critical amount of myocardial damage has taken place.

40. IMAGING ASSESSMENT OF
CARDIAC FUNCTION
• Modalities
• Radionuclide ventriculography (RVG, MUGA)
• Computed Tomography (CT)
• Echocardiography
• Cardiovascular Magnetic Resonance (CMR)

41. IMPROVED REPRODUCIBILITY
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42. CARDIAC BIOMARKERS
• Troponins, has proven to be a more sensitive and more specific
tool for early, real-time identification, assessment and
monitoring of anticancer drug induced cardiac injury.
• Strong data indicate that troponin detects anticancer drug
induced cardiotoxicity in its earliest phase, long before any
reduction in LVEF has occurred.
Cardinale D, Sandri MT, Colombo A et al. Prognostic value of Troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004; 109:2749–
2754.

43. CARDIAC BIOMARKERS
• In patients treated with trastuzumab, troponin might help us
to distinguish between reversible and irreversible cardiac
injury by identifying myocardial cell necrosis.
• The measurement of troponin immediately before and
immediately after each cycle of cancer therapy seems to be
effective enough.
Cardinale D, Colombo A, Torrisi R et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of
troponin I evaluation. J Clin Oncol. 2010; 28: 3910–3916

44. PREVENTION OF ANTICANCER
DRUG-INDUCED LVD
• According to the American College of Cardiology and American
Heart Association guidelines, patients receiving chemotherapy
may be considered a Stage A HF group, namely those with an
increased risk of developing cardiac dysfunction*.
• Carvedilol may prevent cardiac damage induced by doxorubicin
due to its antioxidant activity.
• The effect of carvedilol was confirmed in a randomized study in
which prophylactic use of carvedilol in a small population of
patients treated with anthracycline prevented LVD and reduced
mortality.
*Eschenhagen T, Force T, Ewer M et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart
Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2011; 13: 1–10

45. PREVENTION
• Asymptomatic LVD should be treated
• ACE-Is should be used in all asymptomatic patients with LVD
and an ejection fraction <40%
• Class I, A for ejection fraction <35%
• Class I, B for ejection fraction 35%–40%
• Also, an ACE-I should be considered if LVEF is <50%
• BB should be considered in all patients with asymptomatic LVD
and an LVEF <40%
• if prior myocardial infarction Class I, B
• if no myocardial infarction Class II, C
Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines
Annals of Oncology 23 (Supplement 7): vii155–vii166, 2012 doi:10.1093/annonc/mds293

46. PREVENTION
• Dexrazoxane, an iron-chelating agent significantly reduces
anthracycline related cardiotoxicity in adults with different solid
tumors and in children with acute lymphoblastic leukemia and
Ewing’s sarcoma.
• Dexrazoxane is not routinely used in clinical practice and it is
recommended as a cardioprotectant by the American Society of
Clinical Oncology only for patients with metastatic breast cancer who
have already received more than 300 mg/m2 of doxorubicin.
Huh WW, Jaffe N, Durand JB et al. Comparison of doxorubicin cardiotoxicity in pediatric sarcoma patients when given with dexrazoxane versus
continuous infusion. Pediatr Hematol Oncol. 2010; 27: 546–557.

47. TREATMENT OF ANTICANCER
DRUG-INDUCED LVD
• All patients with cancer who are treated with potentially
cardiotoxic therapy represent a high-risk group for the
development of HF.
• These patients have been excluded from large randomized
trials evaluating the effectiveness of angiotensin-converting
enzyme inhibitors (ACE-I) and beta- blocking agents (BB).

48. • Recent findings reported in a large population of anthracycline
induced CMP patients demonstrated that the time elapsed from
the end of chemotherapy to the start of HF therapy (time-to-
treatment), with ACE-I and, when tolerated, with BB, is a crucial
variable for recovery of cardiac dysfunction*.
• Indeed, the likelihood of obtaining a complete LVEF recovery is
higher in patients in whom treatment is initiated within 2
months from the end of chemotherapy.
• Although promising data have been published, convincing
evidence from large randomized and prospective trials is still
needed.
*Cardinale D, Colombo A, Sandri MT et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-
converting enzyme inhibition. Circulation. 2006; 114: 2474–2481

49. • Treatment of trastuzumab related cardiotoxicity (TIC) is a more
controversial issue.
• Guidelines are specifically focused on the
continuation/withdrawal/resuming of trastuzumab therapy.
• No evidence based recommendations for the treatment of patients
developing cardiac dysfunction after trastuzumab therapy have been
proposed.
• The evidence that support the use of ACE-I and BB in this setting is
limited to case series.

50. TREATMENT OF LVD INDUCED BY ANTICANCER
TREATMENT WITH NON-REVERSIBLE (TYPE I) OR
REVERSIBLE (TYPE II) CARDIOTOXICITY

51. …THANK YOU…