Cardiac Toxicity in Oncology: Why and When

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Cardiac Toxicity in OncologyWhy and When

• Sean Hopkins
• The Ottawa Hospital Regional Cancer Centre
• CSHP PPC 2005

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Review of Goals Objectives

• To provide information on the cardiac risks of
  chemotherapy and the various agents that are
  associated with cardiac dysfunction
• To provide pharmacists with examples of the
  various chemotherapy regimens that are associated
  with cardiac toxicity and their efficacy, along
  with their role in therapy

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Review of Goals Objectives

• To introduce newer agents and combinations that
  are under investigation for cancer treatment
• Focus will be on Breast Cancer therapy, but the
  toxicities can be translated in many other cancers

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Cardiac Toxicity Why ?

• Why do we risk Cardiac toxicity ?
• Why do we accept ANY toxicity in Oncology ?
• An acceptable risk
• 50-90 of patients experience Nausea and vomiting
• 10-100 of patients experience alopecia
• 0-100 of patients experience bone marrow
  suppression
• No other discipline allows this degree of
  toxicity
• Balance of risk vs benefit

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Cardiac Toxicity Why ?

• Adjuvant therapy improves survival
• Improved survival means that more women are alive
  after being diagnosed and treated for early
  breast cancer (EBC)
• Therefore, more women will be at risk of
  experiencing long-term toxicities from therapy
• Cardiotoxic drugs are a cornerstone of adjuvant
  therapy in breast cancer
• Also very important in Lymphomas (Hodgkin's and
  Non-Hodgkin's) as well as leukemias.

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Overview of therapy of solid tumors

• Surgery
• Only definitive action in solid tumors makes
  largest impact on survival
• Local Therapy (radiotherapy)
• Reduces risk of local recurrence
• Hormonal therapy
• Reduces risk in hormone receptor positive tumors
  (60 breast cancer)

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Overview of therapy of solid tumors Breast
Cancer

• Systemic Chemotherapy
• Reduces risk of recurrence of disease distantly.
• Many Regimens and Abbreviations
• FAC (Fluorouracil, Doxorubicin, Cyclophosphamide)
• TAC (Docetaxel, Doxorubicin, Cyclophosphamide)
• CEF (Cyclophosphamide, Epirubicin, Fluorouracil)
• FEC (Fluorouracil, Epirubicin, Cyclophosphamide)
• AC (Doxorubicin, Cyclophosphamide)
• AC -gt T (AC followed by Paclitaxel)
• CMF (Cyclophosphamide, Methotrexate, Fluorouracil)

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Adjuvant Therapy How Effective is it ?

• Absolute benefit of 6 in Overall Survival

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Adjuvant Therapy How Effective is it ?

• NCIC MA.5 Trial (CEF vs CMF)
• 7 absolute increase in survival
• gt50 of patients are alive and free of disease at
  10 years
• FASG (see next slide)
• Online resource for risk analysis
• www.adjuvantonline.com

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Efficacy of FEC100 Overall Survival

• FASG05 (FEC100 vs FEC50)
• 12 absolute increase in survival
• J Clin Oncol 19602-611 2001

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Efficacy of Combinations in Metastatic disease

• The addition of trastuzumab to chemotherapy was
  associated with
• A longer time to disease progression (median, 7.4
  vs. 4.6 months Plt0.001)
• A higher rate of objective response (50 percent
  vs. 32 percent, Plt0.001)
• A longer duration of response (median, 9.1 vs.
  6.1 months Plt0.001)
• A lower rate of death at 1 year (22 percent vs.
  33 percent, P0.008)
• Longer survival (median survival, 25.1 vs. 20.3
  months P0.046) and
• A 20 percent reduction in the risk of death.

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Cardiac Toxicity

• What is Cardiac Toxicity ?
• NCI CTC (National Cancer Institute Common
  Toxicity Criteria)
• Normally most concerned with Left Ventricular
  Ejection Fraction (LVEF)
• Arrhythmias do occur, but most important
  long-term toxicity is decreased LVEF, resulting
  in Heart Failure

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Cardiac Toxicity

• A cardiac clinical sign
• CHF, rhythm disorders, angina, thromboembolic
  disease, or hypertensive cardiopathy
• a cardiac event between the end of chemotherapy
  and the present cardiologic consultation
• an abnormal ECG
• an LVEF less than 50,
• a decrease in LVEF 20 of baseline value or
• an abnormal ultrasonographic parameter

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Drugs that cause cardiac toxicity

• Anthracyclines / Anthracenediones
• Doxorubicin / Daunorubicin / Epirubicin
• Idarubicin
• Mitoxantrone
• Liposomal formulations of above

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Relative risk of Cardiac Dysfunction

• Doxorubicin relative value 1 5 incidence of
  cardiotoxicity _at_450mg/m2
• Daunorubicin, 10.5, 5 cardiotoxicity _at_900mg/m2
• Epirubicin, 10.5, 5 cardiotoxicity _at_935mg/m2
• Idarubicin, 12, 5 cardiotoxicity _at_225mg/m2
• Mitoxantrone, 12.2, 5 cardiotoxicity _at_200m/m2

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Drugs that cause cardiac toxicity

• Taxanes
• Paclitaxel / docetaxel
• Especially in combination with anthracyclines
• Sequencing can affect cardiac toxicity
• Miscellaneous
• Fluorouracil
• Etoposide

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Drugs that cause cardiac toxicity

• Monoclonal Antobodies
• Primarily trastuzumab (Herceptin)
• Potential with bevacizumab (Avastin)
• Both have synergistic increases in cardiac
  toxicity when combined with an anthracycline
  (investigated in sarcomas)
• Alemtuzumab (Campath-1H)
• Small group of patients reported a 50 cardiac
  toxicity rate

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Combinations

• Combinations of drugs increase risk
• Sequencing of drugs may affect toxicity
• PK interactions
• Synergistic MOA for cardiac toxicity (NEJM 2001)
• AC trastuzumab -gt 27 cardiac toxocity
• AC -gt 8 cardiac toxicity
• Paclitaxel trastuzumab -gt 13
• Paclitaxel -gt 1

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Why do we want to risk it ?

• Response rate was highest in arm that contained
  AC trastuzumab
• Complete partial response 80 c.f. 38 with
  paclitaxel trastuzumab
• AC alone 58 cf 16 for paclitaxel alone
• Other studies have shown 80-90 RR for
  anthracycline trastuzumab

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Mechanism of Cardiac Toxicity

• Extrinsic Pathways
• Pro-apoptotic pathways are activated by
  anthracyclines and other drugs
• Intrinsic pathways
• Cytochrome C release by mitochondria induces
  caspase-9 activity which signals apoptosis
• Probable role of iron / ferritin / reactive
  oxygen species and incomplete oxidation in
  inducing cytochrome C release

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Extrinsic Pathway Akt
Possible explanation for monoclonal
antibody-mediated cardiac toxicty
http//www.biocarta.com
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Mechanism of Cardiac Toxicity

• Trastuzumab
• Unknown mechanism
• HER/2-neu (c-erbB-2) not overexpressed in cardiac
  tissue
• May be related to inhibition of anti-apoptotic
  pathways
• Bevacizumab
• Unknown too new on market (in US only)

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Intrinsic Pathway - Mitochondria
Mitochondria play a more significant role in
apoptosis than previously recognized and are the
primary target of cardiac toxicity from
anthracyclines
http//www.biocarta.com
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Mechanism of Cardiac Toxicity

• Taxanes
• Unknown mechanism
• PK interaction with anthracyclines increases
  production of inactive, cardiotoxic metabolite

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Preventing cardiac toxicity

• Administration
• Prolonged infusions are less cardiotoxic than
  rapid IV infusion
• Splitting dose over multiple administrations per
  week or weekly
• Antioxidants
• May bind up reactive oxygen species generated by
  inefficient respiration in mitochondria

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Preventing cardiac toxicity

• Iron chelators (Dexrazoxane)
• Chelates Fe3 reduces production of reactive
  oxygen
• At 101 ratio of dexrazoxane doxorubicin there
  is no interaction (PK,PD)
• At 101 ratio of dexrazoxane epirubicin in high
  doses, AUC of epirubicin decreased
• Potential for reduced efficacy
• In clinical practice, with doses of epirubicin of
  100 mg/m2 I suggest ratios of 6.251 (safer and
  effective)

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Preventing cardiac toxicity

• Liposomal formulation
• Reduced risk for cardiac toxicity but does not
  disappear entirely
• May allow for prolonged administration of an
  anthracycline when effective while reducing
  cardiac toxicity

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Efficacy in preventing cardiac toxicity -
dexrazoxane

• Meta analysis showed a hazard ratio of 0.21 in
  favor of dexrazoxane over placebo in preventing
  toxicity (Relative risk reduction of 79)
• Still, a small fraction of patients may
  experience cardiotoxicity (lt1 CHF, lt15 other)
  despite therapy with dexrazoxane

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Therapy for Cardiac Toxicity

• Symptomatic / Standard for CHF
• ACEi, Beta-Blockers, etc.
• Some toxicity resolves over time
• We have a current pt with LVEF of 24 after 6
  cycles of CEF
• Pt is symptomatic (SOB, decreased exercise
  tolerance)
• No resolution of symptoms 6 months post therapy

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When can cardiotoxicity occur

• Actuarial risks
• At a cumulative dose of doxorubicin of 300mg/m2
  (6 cycles of FAC chemotherapy) risk is less than
  1
• _at_500-550mg/m2, 4 risk
• _at_551-600mg/m2, 18 risk
• _at_601 mg/m2, 36 risk
• Theoretical maximum dose of 500-550 mg/m2 used

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Cardiac Toxicity with CHOP Chemotherapy
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Different anthracyclines

• Epirubicin
• Epimer of doxorubicin
• Can be used in 21 ratio for improved efficacy
• Relative cardiotoxicity risk is 11.8-2.0 wrt
  doxorubicin
• Theoretical maximum of epirubicin is
  800-1000mg/m2
• Mitoxantrone
• Maximum lifetime dose 140 mg/m2
• No efficacy data in preventing cardiac toxicity
  with dexrazoxane

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When can cardiotoxicity occur

• Risk factors for developing cardiac toxicity
• Valvular heart disease
• Coronary / myocardial heart disease
• Long-standing hypertension
• Mediastinal irradiation
• Reduced with more modern radiotherapy planning
  techniques

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When can cardiotoxicity occur

• Reality is that a single dose of 50 mg/m2 of
  doxorubicin has caused florid CHF
• Patients have also tolerated over 1000mg/m2
  without toxicity
• Timeline ?
• Acute (during therapy)
• Long-term (in follow-up)

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When can cardiotoxicity occur

• Acute (during active therapy)
• Rare, but a significant morbidity during adjuvant
  therapy
• Infrequent but not unexpected in therapy of
  metastatic disease with trastuzumab
• Long-term
• Delayed appearance of cardiac toxicity
• May start 6 months after therapy to years later

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Cardiac toxicity in Adjuvant Chemotherapy
for Breast Cancer

• FASG05
• At 8 years, 2.3 CHF rate, higher rate of
  asymptomatic decline in LVEF
• AC Chemotherapy (NCCTG N9831)
• 1458 pts evaluated for LVEF
• 51 had asymptomatic decreases in LVEF
• 2.5-2.9 of patients had more severe reduction in
  LVEF

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Childhood Cancers

• Long-tern cardiac toxicity for survivors of
  childhood leukemia
• 10-15 years out from therapy, cardiac toxicity
  may occur
• There may be physiologic factors as of yet
  determined that reduce the risk of developing
  cardiac dysfunction.

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Investigational approach to preventing
cardiac toxicity

• Prevent inactivation of extrinsic pathways
• Akt inactivation prevented in vitro by Eprex
• Neuregulin (ligand for c-erbB-2) prevents
  inactivation of Akt pathway
• Prevent activation of intrinsic pathways
• L-Carnitine blocks release of cytochrome c,
  activation of caspase-9
• May prevent cardiac toxicity

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Conclusion

• Overall, risks for cardiac toxicity is low with
  normal doses of anthracyclines
• 6 x cycles of FEC100 (600 mg/m2 Epi)
• 4 x cycles of AC (240 mg/m2 Doxo)
• 6 x cycles of TAC (300 mg/m2 Doxo)
• 6 x cycles of CEF (720 mg/m2 Epi)
• Long-term incidence of cardiac toxicity is a
  concern if many more breast cancer patients are
  exposed to cardiotoxic therapy

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• Questions ?
• Handouts available at
• www.cshpontario.cawww.supportivecare.ca