This document summarizes the cardiac toxicities of various chemotherapy drugs. It discusses how cardiac myocytes have limited regenerative capacity, making them susceptible to permanent damage from chemotherapy. Several classes of drugs are associated with cardiac toxicity, including anthracyclines, alkylating agents, antimicrotubule agents, antimetabolites, targeted therapies, and hormones. Specific drugs like doxorubicin, trastuzumab, and imatinib can cause heart failure, arrhythmias, and other issues. The document provides details on mechanisms, risk factors, management strategies, and prevention methods for chemotherapy-induced cardiac toxicity.

1. CARDIAC TOXICITY OF
CHEMOTHERAPIES
JOYDEEP GHOSH

2. 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

3. Drugs…
• Anthracyclins , anthraquinones
• Bleomycin, mitomycin C
• Etoposide
• Alkylating agents
• Antimicrotubule agents
• Antimetabolites
• ATRA, arsenic
• Targeted therapy agents, esp herceptin

4. Anthracyclins..
• Once developed, carries poor prognosis and
often fatal
• Types:
– Acute and subacute
– Chronic

5. Acute…
• Develops in 2-3 days , can be prolonged upto
weeks 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

6. 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

7. • Most important factor is DOSE
• Incidence is dose dependant:
• Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA: A clinicopathologic
analysis of Adriamycin cardiotoxicity. Cancer 1973; 32: 302–314
500-550/m2 4%
551-600/m2 18%
>600 36%

8. 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

9. Histopathology…
• Patchy myocardial interstitial fibrosis with
scattered vacuolated myocytes – ADRIA cells
• Fibroblastic proliferation and histiocytic
infiltration
• Partial / total loss of myofibrils and vacuolar
degeneration is essential
• Distension of sarcoplasmic reticulum

10. 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

11. Mechanism??

12. 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

13. • 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

14. • 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

15. Doxorubicin in lymphoma ..
Total 141 pts
Average dose 250 – 550 /m2
Results:
Clinical CHF: only 1 pt
Subclinical decline in LVEF <25% of baseline: 28%
Risk factor analysis: AGE and MALE SEX to be the most
significant factor

16. 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

17. 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

19. Kanu chatterjee et al…

21. 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.

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

23. • 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)

24. 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%

25. 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

26. 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

27. 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

28. 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

29. 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

30. • Acute onset fulminant CHF is seen in 29%
cases of high dose therapy
• Mx:
– diuretics,
– ACEI,
– Beta blockers,
– inotropic medications

31. • 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

32. 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

33. Docetaxel..
• Conduction abnormalities, cardiovascular
collapse, and angina
• Evidence does exist for a potentiating effect of
anthracycline cardiomyopathy

34. 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%

35. • 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.

36. • 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

37. 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

38. • 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

39. • 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

40. Trastuzumab..
• The incidence rates were
– 2% sincle agent
– 13% + paclitaxel
– 27% + anthracycline

42. 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 ultrastructural
alterations within the myocardium

43. Management..
• If asymptomatic decline in LVEF:
– ACEI/ARBs/beta blockers stop herceptin
• If symptomatic
– Diuretics add on

44. 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