CHEMOTHERAPYINDUCED

CARDIOTOXICITYDr. VISHAL VANANI

Jaslok Hospital, Mumbai

• 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

• 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; 339:900

CARDIOTOXIC CHEMOTHERAPY

• Interleukins• Interferons

• Anthracyclines

• Antimetabolites• Antimicrotubules• Monoclonal Antibodies

• Tyrosine kinase inhibitors

• Alkylating agents

• Arsenical Compounds

• 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

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.

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.

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

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

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; 125:47Steinberg 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

• 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

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.

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

ANTHRACYCLINES: MAXIMUM “SAFE” DOSES

Drug Dosedoxorubicin 550 mg/m2

danorubicin 600 mg/m2

epirubicin 1000 mg/m2

idarubicin 100 mg/m2

Mitoxantrone 160 mg/m2

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

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

• 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 elevatedalternative 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%

ANTHRACYCLINES:PREVENTION

• Altering infusion protocol• Alternate anthracycline derivatives• Liposomal preparations • Dexrazoxane - metal-chelating agent • Beta-blockers• ACE inhibitors

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.

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.

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

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

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

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

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

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.

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

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®)

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.

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

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

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.

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

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

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

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

• 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.

IMAGING ASSESSMENT OF CARDIAC FUNCTION

• Modalities• Radionuclide ventriculography (RVG, MUGA)• Computed Tomography (CT)• Echocardiography• Cardiovascular Magnetic Resonance (CMR)

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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.

Pichon MF, Cvitkovic F, Hacene K et al. Drug-induced cardiotoxicity studied by longitudinal B-type natriuretic peptide assays and radionuclide ventriculography. In Vivo. 2005; 19: 567–576

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

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

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

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.

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).

• 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

• 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.

TREATMENT OF LVD INDUCED BY ANTICANCER TREATMENT WITH NON-REVERSIBLE (TYPE I) OR

REVERSIBLE (TYPE II) CARDIOTOXICITY

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