To confront cancer is to encounter a parallel species, one perhaps more adapted to survival than even we areit is not simply

a clonal disease; it is a clonally evolving disease.

-Siddhartha Mukherjee

Anthracycline Induced Cardiomyopathy Morning Report

Devin Horton, R3 Internal Medicine/Pediatrics

History of Medicine

MEDICINE

TIME

Edwin Smith Papyrus 3000 BC

(10)

Carcinos: Greek Crab

(10)

Latin Cancer

(10)

460-375 BC

25 BC- 50 AD

1845 German Leukamie Greek Leukos=White, Aima=Blood

(10)

Rudolf Virchow

Chemotherapy 1947

(9)

Leukemia: Most common form of cancer in children

~30% of all childhood malignancies

End Results in Cancer, Report No. 2

1 year survival rate of patients with acute leukemia under 20 years of age 1940-44: 4% 1950-54: 14% 1955-59: 29%

Streptomyces Peucetius Castel Del Monte: Italy 1950s

(14)

Anthracycline: -Class of cancer chemotherapy that Inhibits DNA/RNA synthesis by Intercalating base pairs -Treats leukemia, lymphoma, BRCA, and several others Ca -One of the most effective anticancer tx ever developed -effective against more types of ca than any other agent (18)

Dauni + Rubis = Daunorubicin

First Studies
Tumori. 1963 May-Jun;49:203-17. [EXPERIMENTAL STUDIES OF THE ANTINEOPLASTIC ACTIVITY OF A NEW ANTIBIOTIC, DAUNOMYCIN]. [Article in Italian] 1967. Preliminary results of the therapeutic effectiveness in leukemia and malignant tumors in children of a new antineoplastic antibiotic: Daunomycin. Italian Lancet. 1969 Apr 19;1(7599):837. Cardiac toxicity of daunorubicin. Bonadonna G, Monfardini S. Progress:
1940-44: 1 Year survival rate = 4% Present: ALL 5 year survival rate >80% AML 5 year survival rate > 65% (1, 2)

New challenges
Treatment of systemic sequelae of chemotherapy 2004 ~250,000 survivors of childhood cancer in USA Only 500 were 20-34 yo in 2010 -> 249,500 are growing up Childhood Cancer Survivor Study:
(15)

30 Years after treatment, the cumulative incidence of chronic health conditions in long term survivors = 73% Cumulative incidence severe, disabling, life threatening conditions or death = 42%
(3)

Anthracycline Cardiotoxicity
300-500mg/m2 Usually seen > 6 years after tx Impaired LV contraction, CHF, Ectopy Increased risk of sudden death from cardiac cause One study: increased cardiac death 8.2 x normal population even 25 years after tx Other: Increased Cardiac death by factor of 5.8, sudden cardiac death factor of 3.9
(15)

Chemical Mechanism

(5, 6)

Fenton

Cellular Mechansim
3.

(5)

1.

2.

Why the Heart?

(5,6)

Cardiac myocytes have low levels of free radical scavenging systems->sensitize these cells to ROS induced injury High affinity for cardiolipin in Mito ->Inhibits respiratory chain; heart has large amount of cardiolipin Interruption of CA channels effects contractility Rapidly dividing cells can replace those lost to apoptosis Cardiomyocytes divide slowly if at all, cannot replace cell damage during treatment

Types of Cardiomyopathy
1. Acute <1% Reversible episode of myocardial dysfunction during therapy Presents as transient clinical heart failure and sinus tachycardia/autonomic dysfxn Resolve once therapy is discontinued 2. Early Onset Chronic Progressive Cardiomyopathy Within 1 year EP changes, LV dysfxn, decreased exercise capacity, heart failure
(6) (6)

3. Late Onset Chronic Progressive Cardiomyopathy

(6)

>1 year after tx Myocyte loss->LV wall thinning->progressive LV dilation Echo: decreased LV fractional shortening, end diastolic posterior wall thickness, mass, contractility, increased LV afterload 115 children, ALL survivors at 6 years: 65% had abnormal LV structure or fxn
Far smaller dose then AML and still cardiotoxic
(8)

Z scores of left ventricular contractility (panel A) and left ventricular mass (panel B) from 115 long term survivors of acute lymphoblastic leukemia treated with doxorubicin, by time since diagnosis.

Lipshultz S E et al. Heart 2008;94:525-533

Non-Modifiable Risk Factors

(6)

AGE: Pts treated at a younger age, especially < 4 Sex: Girls at significantly greater risk for late depressed contractility with same dose Sex specific body fat may be a factor Genetic factors: Mutations effecting iron metabolism Mice with hemochromatosis more sensitive May 2012 Journal of Clinical Oncology
Polymorphisms of reductive Enzyme-> 100150mg/m2
(16)

Modifiable Risk Factors

(6)

Cumulative dose: >300: >500mg/m2-> 5x more likely then lower doses No safe dose.
Even lowest clinically relevant dose can cause cardiac dysfunction

Must be balanced with oncologic efficacy Concomitant treatment (Radiation/Cyclophosphamide, Bleo, etc) Liposomal forms? Rate of administration = controlling peak serum conc Prolonged infusion became standard before confirmation of RCT Lipshultzs randomized trial in 2002 (11)
showed no benefit of prolong infusion vs. Bolus infusions Prolonged hospitalization increase costs and stress

Monitoring

(15)

Increase trop (>0.01) in first 90 days of tx significantly associated with Lower LV mass and LV end-diastolic posterior wall thickness 4 years later (P< 0.01) Increase BNP in first 90 days significantly associated with abnormal LV thickness to dimension ratio at 4 years (P=0.01) Echo lack sensitivity to detect early injury and specificity to detect long term damage vs. acute/transient changes (cytokine effects)

Cardioprotectants/Treatment
Symptomatic treatment is important but may be delaying progression ACE: reduce LV afterload and slow progression of LV dysfunction In study of enalapril on long term effect on childhood cancer survivors Initial significant improvement in LV mass, dimension, afterload Gains lost after 6-10 years After 6 years, all those who started with CHF had progressed to transplant or death
(6) ( 13)

Cardioprotectants

(6)

Most effective: prevent initial damage Many drugs tested (primarily decrease ROS) Most promising Dexrazoxane Similar to EDTA Chelates intracellular iron Inhibits anthracycline-iron complexes responsible for generating myocardiocyte damaging ROS Approved in 2002 by FDA in women with metastatic breast cancer who need large doses Kids? -> 2004 Randomized trial in children with ALL showed significantly less acute elevation of troponin levels (12)

Percentage of patients with at least one elevated serum cardiac troponin T level overall, before and during treatment with doxorubicin for ALL.

Lipshultz S E et al. Heart 2008;94:525-533

Copyright BMJ Publishing Group Ltd & British Cardiovascular Society. All rights reserved.

Dexrazoxane: 4/2012
Y: Proportion of samples with detectable troponin, BNP, CRP X: Months since random assignment N: 75 D 81 D & D

(15)

Trop: no diff baseline

1.8 months after: D sig higher than DD until end of tx BL BNP same Tx: 83->35% D 87->16% DD After: D increase DD: decreased

Dexrazoxane

Why not abandon Anthracylcine altogether?

(14)

Superior disease-free survival rates with anthracyclines -> limits other tx options Doxorubicin (DOX) differs from daunorubicin (DNR) only by a single hydroxyl group Five DOX/DNR analogs marketed in other countries, one (idarubicin) is available in the United States None of the analogs have stronger antitumor efficacy than the original two anthracyclines
(6)

What do we do at PCMC?

(17)

Only protocol that defines Dexrazoxane use is active Ewings TX study->all get it when dose reaches 300mg/m2
All other, attending dependent

All pts get echo after each 150mg/m2 of anthracycline Cumulative dose >450 ->echo before each dose Echos q 1-5 years based on Childrens Oncology Group guidelines Anything abnormal->urgent cards consult who usually start ACE-I Trops not used outside of research

Continuing Studies

(6)

Growth Hormone Beta Blockers Statins Heart healthy diet, Na, obesity, DM control, smoking Exercise

Conclusion
Treatment for Acute Leukemia has come a long way Childhood cancer survival has led to new complications including cardiotoxicity Though cumulative anthracycline dose is important, there is no safe dose Many cardiac complications are late onset and thus these pts must be monitored and followed for the long term Cardiac markers may predict CT but would it change management Dexrazoxane may have more of a role then previously thought We as pediatricians and Internists will be treating a population completely different from those ever seen before

Thanks to
Dr. Jenny Wright Gabrielle Zimbric Arlette Priego

References

1. Alvarez J, Scully R, Miller T, et al. Long-term effects of treatments for childhood cancers. Curr Opin Pediatr 2007;19:2331 2. Ten-year survival of children with acute lymphoblastic leukemia: a report from the Children's Oncology Group. AU, Trigg ME, Sather HN, Reaman GH, Tubergen DG, Steinherz PG, Gaynon PS, Uckun FM, Hammond GD, Children's Oncology Group, SO, Leuk Lymphoma. 2008;49(6):1142 3. Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 2001;19:31634. Moller TR, Garwicz S, Barlow L, et al. Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries. J Clin Oncol 2001;19:317381. 5. J.Mol Cell Cariol2012 Mar 21. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies .Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. 6. Heartheart.bmj.com, Heart 2008;94:525-533 doi:10.1136/hrt.2007.136093 , Education in Heart, Clinical pharmacology, Anthracycline associated cardiotoxicity in survivors of, childhood cancer. Steven E Lipshultz1, Jorge A Alvarez2, Rebecca E Scully2 7. Pathogenesis of cardiotoxicity induced by anthracyclines. Elliott P. Semin Oncol. 2006;33(3 Suppl 8):S2. 8. Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991;324:80815. 9. The Emperor of All Maladies: A Biography of Cancer, by Siddhartha Mukherjee 10. Hajdu, SI (2011-03-01). "A note from history: landmarks in history of cancer, part 1.". Cancer 117 (5): 1097102. 11. Lipshultz SE, Giantris AL, Lipsitz SR, et al. Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 acute lymphoblastic leukemia protocol. J Clin Oncol 2002;20:167782. 12. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004;351:14553. 13. van Dalen EC, Caron HN, Kremer LC. Prevention of anthracycline-induced cardiotoxicity in children: the evidence. Eur J Cancer 2007;43:113440. 14. Semin Oncol. 1992 Dec;19(6):670-86. The anthracyclines: will we ever find a better doxorubicin? Weiss RB. 15. Lipshultz, Changes in cardiac Biomarkers During Doxorubicin Treatment of Pediatric Patients with High-Risk ALL: Assocations with long-Term Echocardiographic Outcomes. Journal of Clinical Oncology; Volume 30, number 10, April, 1, 2012 16. Blanco et al. Anthracycline-related Cardiomyopathy after childhood cancer: Role of polymorphisms in carbonyl reductase genes A report from the Childrens Oncology Group, Journal of Clinical Oncology, volume 30, page 1315, May 1, 2012 17. Jenny Wright 18. Wikipedia

Questions?
It is often said that the Buddha's teaching is a finger pointing to the moon. Don't mistake the finger for the moon itself. -Thich Nhat Hanh