CARDIAC TOXICITY OF CHEMOTHERAPIES

JOYDEEP GHOSH

Introduction…

• With the improvement in cancer care- the concern for toxicity comes into play

• Cells which are rapidly dividing– bear the brunt of major toxicities

• Cardiac myocytes have limited regenerative capacity

• So, they are susceptible to permanent side effects

Drugs…

• Anthracyclins , anthraquinones

• Bleomycin, mitomycin C

• Etoposide

• Alkylating agents

• Antimicrotubule agents

• Antimetabolites

• ATRA, arsenic

• Targeted therapy agents, esp herceptin

Anthracyclins..

• Once developed, carries poor prognosis and often fatal

• Types:

– Acute and subacute

– Chronic

Acute…

• Develops in 2-3 days , can be prolonged uptoweeks in subacute variety

• Incidence– 11%

• C/o: chest pain, palpitations

• Patho: myopericarditis, due to edema of myofibrils and pericardial mesothelium

• ECG: PSVT, sinus tachy, premature atrial and vent complexes

• Acute LVF: very rare but usually reversible

Chronic..

• Incidence much lower: 1.3%

• It is usually evident within 30 days of administration of its last dose, but it may occur even after 6–10 years after its administration

• Risk factors:– other cardiotoxic agents, mediastinal RT

– Extremes of age

– Prior CV morbidity

• Most important factor is DOSE

• Incidence is dose dependant:

• Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA: A clinicopathologicanalysis of Adriamycin cardiotoxicity. Cancer 1973; 32: 302–314

500-550/m2 4%

551-600/m2 18%

>600 36%

Morphology and functional changes

• Similar to those of dilated cardiomyopathy

• All 4 chambers are usually dilated

• LVEF and inotropy is reduced

• Concomitant elevation of LVEDP due to diastolic failure

• Wall stress is increased as there is no significant hypertrophy

• Mural thrombi may be present

Histopathology…

• Patchy myocardial interstitial fibrosis with scattered vacuolated myocytes – ADRIA cells

• Fibroblastic proliferation and histiocyticinfiltration

• Partial / total loss of myofibrils and vacuolar degeneration is essential

• Distension of sarcoplasmic reticulum

A :Normal myocardium with little or no extracellular matrix changes and intact myocytes.

B: Same features in higher magnification.

C: Myocyte loss, matrix disorganization and diffuse fibrosis

Mechanism??

DIAGNOSIS

• History and physical examination– Elevated JVP

– S3 gallop

• ECG: nonspecific ST-T changes with low voltage QRS complexes

• CXR, echo

• Radionuclide ventriculography has been used to assess LV systolic and diastolic function– Impaired glucose and fatty acid metabolism has been

observed in doxorubicin cardiomyopathy

• Antimyosin antibody study with the use of 111 In-labeled monoclonal antimyosin antibody is used for the diagnosis of myocarditis and has also been employed for the diagnosis of doxorubicin cardiomyopathy

• Highly sensitive

• Annexin V, which has high affinity for membrane -bound phosphatidylserine, has been used to detect apoptosis induced by doxorubicin

• In case of CHF, cardiac troponins and BNP are useful

• The endomyocardial biopsy may reveal characteristic diagnostic features of doxorubicin cardiomyopathy.

• Required for diagnosis are:– loss of myofibrils,

– distention of sarcoplasmic reticulum

– vacuolization of the cytoplasm

Doxorubicin in lymphoma ..

Total 141 ptsAverage dose 250 – 550 /m2Results: Clinical CHF: only 1 ptSubclinical decline in LVEF <25% of baseline: 28%Risk factor analysis: AGE and MALE SEX to be the most significant factor

Management..

• No specific therapy

• Metoprolol is safe and effective

• ACEI, diuretics when HF develops

• ICD – in case of arrythmia and LVEF <40 with NYHA 3-4 symptomatology

Prevention..

• Major emphasis has been to limit the cumulative dose of doxorubicin to <450 mg/m2

• continuous slow infusion

• Most of the pharmacologic agents that have been tested to reduce or prevent doxorubicin cardiotoxicity have the potential to reduce oxidative stress

Kanu chatterjee et al…

Dexrazoxane..

• Used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced breast cancer)

• MOA: iron chelation in the cells.

Journal of Clinical Oncology,Vol 17, No 10 (October), 1999: pp 3333-3355

• 101 pts in doxo alone arm/ 105 pts in doxo+dexra arm• Median cumulative dose of doxo: 300mg/m2• Method: serial monitoring of Trop t in both the groups• Results:

– Trop T elevation in 35%pts– Elevated trop T levels (50% vs 21%, P<0.001)– extremely elevated troponin T levels (32 percent vs. 10 percent, P<0.001)– Median follow up is 2.5 yrs– Rate of event-free survival at 2.5 years was 83 percent– in both groups (P=0.87 by the log-rank test)

Anthraquinones…

• Mitoxantrone is an anthraquinone designed to yield broad spectrum antitumor activity similar to the anthracyclines

• Phase I and phase II studies -- dose-related cardiac failure and arrhythmias

• Doses greater than 160/ mg/m2

• Incidence:• Subclinical mod to severe decline: 13%

• Overt cardiac failure: 2.3%

Other drugs..

• Vinca alkaloids:

– Hypertension, myocardial ischemia, myocardial infarction, and other vaso-occlusive complications have been implicated with the use of these drugs

– Most common agent is vinblastine

» Harris AL, Wong C. Myocardial ischaemia, radiotherapy, and vinblastine. Lancet 1988;8223:787

» Mandel E, Lewinski U, Djaldetti M. Vincristine-induced myocardial infarction. Cancer 1975;36:1979-1982

Mitomycin C, Bleomycin

• Mito C: cumulative doses greater than 30 mg per m2

• In one report, 5 of 15 patients treated with mitomycin C had myocardial changes that histologically resembled radiation-induced cardiac injury

• Ravry MJ. Cardiotoxicity of mitomycin C in man and animals. Cancer Treat Rep 1979;63:555

Bleomycin

• Pericarditis is an uncommon, but potentially serious, cardiotoxicity

• An acute chest pain syndrome • incidence is less than 3%

• sudden substernal chest pain

• treatment is supportive and discontinuation of the drug is not needed

• May also cause • CAD

• ACS

Topoisomerase II inhibitors

• Etoposide:

– myocardial infarction and vasospastic angina• Schwarzer S, Eber B, Greinix H, et al. Eur Heart J

1991;12:748-750

• Additionally, etoposide is often a part of bleomycin- and cisplatin-based regimens that have been associated with cardiac toxicity

ALKYLATING AGENTS

• At low doses, cyclophosphamide has not been reported to be associated with cardiotoxicity

• Acute cardiac toxicity - doses of 120 to 170 mg per kg over 1 to 7 days as in high dose conditioning regimens for BMT

• Manifestations:– Low voltage QRS

– Nonspecific ST-T changes

– Tachyarrythmia

– CHB

• Acute onset fulminant CHF is seen in 29% cases of high dose therapy

• Mx:

– diuretics,

– ACEI,

– Beta blockers,

– inotropic medications

• Other complications:– Hemorrhagic myopericarditis

• Pathophysiology: endothelial injury

• Onset: usually 1st week of therapy

• Fortunately, most of the effusions can be treated with corticosteroids and analgesics without serious sequelae

Paclitaxel– cardiac arrhythmias, including an asymptomatic

bradycardia that is reversible

– In one phase II study of 45 patients, 13 of the patients treated with paclitaxel developed bradycardia and 2 patients progressed to a higher grade heart block

– It has been suggested that the maximum cumulative doxorubicin dose should be decreased to less than 380/ mg/m2 when it is used in combination with paclitaxel

– Albumin-bound paclitaxel appears to have the same cardiac toxicity as nonalbumin-bound paclitaxel

Docetaxel..

• Conduction abnormalities, cardiovascular collapse, and angina

• Evidence does exist for a potentiating effect of anthracycline cardiomyopathy

Antimetabolites.

• Since then, 5-FU has become the most widely investigated antineoplastic agent known to cause myocardial ischemia

• Ischemic events are more common when this agent is administered in combination with cisplatin

• In a large study of 1140 pts, incidence was 3.1%

• 50% of all patients treated with 5-FU have nonspecific changes on ECG, and

– up to 16% of patients demonstrate ST-T changes

• Precordial chest pain, both anginal and noncardiac, has been reported in patients during continuous drug infusion.

• Rhythm disturbances: vent ectopy, AF

• Mostly occur during 2nd or subsequent infusion

• Symptoms improve with

– Termination of infusion

– Nitrates/CCB

• Prophylactic use of CCB is helpful in prevention

Differentiating agents..

• ATRA:– Approximately 10% to 15% of patients develop a

retinoic acid syndrome (RAS), manifested by fever, dyspnea, pleural effusions, pericardial effusions (with potential for cardiac tamponade), pulmonary infiltrates, peripheral edema, and myocardial ischemia/infarction

• ATO: – prolongation of the QT interval in as high as 63% of

patients and

– Torsades de pointes

• Arsenic induced tachyarrythmia is often drug resistant

• Treatment with parenteral potassium and magnesium, maintaining high normal levels, may be beneficial( K- 4meq/L, Mg- 2mg/dl)

• Specifically, electrolyte and ECG with QT measurement must be obtained before initiating therapy and once or twice weekly during treatment

• Pretreatment QTc should be <500ms

• Arsenic should be discontinued and corrective measures to be started

• If QTc does not correct to <460ms, treatment should be withheld with arsenic

Trastuzumab..

• The incidence rates were

– 2% sincle agent

– 13% + paclitaxel

– 27% + anthracycline

How different from other cardiotoxicities??

• Is not dose-dependent,

• Its clinical manifestations vary between patients,

• It may be reversible, and

• It apparently does not cause ultrastructuralalterations within the myocardium

Management..

• If asymptomatic decline in LVEF:

– ACEI/ARBs/beta blockers stop herceptin

• If symptomatic

– Diuretics add on

Other drugs..Rituximab Arrhythmias Few reported infusion-related

deaths secondary to cardiogenic shock

Bevacizumab MI, CVA Risk factors:age >65, prior MI, CVA

Alemtuzumab CHF, arrhythmias Possibly related to T-cell cytokine release

Cetuximab CHF, arrhythmias, Myocardial infarction/ischemia

Four identified cases, all have been in patients concurrently receiving 5-FU

Sorafenib Myocardial ischemia/infarction

Risk factors and incidence unknown

Sunitinib malate CHF

Imatinib mesylate CHF

Hormone: Diethylstilbestrol Vasospasm Seen at doses >5 mg/d