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Dexrazoxane - use in the paediatric oncology patient

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Anthracycline-induced cardiac damage in childhood cancer

Successive improvements in treatment for paediatric malignancy have led to dramatically improved survival over the past 40 years. Along with the ongoing drive to increase survival rates, there has emerged a parallel drive to improve the quality of survivorship for those cured of their childhood cancer. Anthracyclines (including doxorubicin, daunorubicin, idarubicin, epirubicin and mitoxantrone) are an important class of anticancer drugs and are used in the treatment of many childhood malignancies. Anthracyclines, however, are known to cause persistent damage to the cardiovascular system of patients who receive them as treatment for cancer1,2. Factors increasing the risk of cardiac toxicity include female sex, younger age and cumulative dose of anthracycline3,4. There is no established "safe" dose of anthracycline with clinical cardiotoxicity reported in some patients receiving even the lowest cumulative doses5,6. Radiation therapy with doses delivered to the heart escalates the risk of cardiac damage7.

Long term cardiac morbidity is largely underestimated by end of therapy echocardiograms. Data from long term cohorts indicates that after an apparent near normalization of many echocardiographic markers in the years after treatment, there is a progressive decline from 5-6 years after diagnosis. The most marked of these is LV contractility. Markers such as LV end-diastolic posterior wall thickness show a progressive decline in Z score from the time of treatment with anthracycline8. It is likely that acute cardiac injury happens at the time of anthracycline use resulting in a reduced cardiac mass which leads to late morbidity as described. Degree of troponin rise during anthracycline administration has been correlated with late cardiac morbidity9.

With between 1 in 500 and 1 in 700 adults now a survivor of childhood cancer, the burden of late cardiac toxicity is likely to rise. The cumulative rate of congestive heart failure rises over time10,11 and the standardized mortality rate for cardiac death in childhood cancer survivors who have received anthracycline may be as much as 8 times the background rate12.

Prevention of cardiac toxicity

The most effective method of reducing toxicity from anthracycline is to omit them altogether. In some malignancies this may be safely achieved13 but it is likely that in most malignancies anthracyclines will remain an important part of treatment. Slowing infusion rate to minimise peak levels of anthracycline has not shown any benefit in childhood cancer treatment14.

Dexrazoxane

Perhaps the most promising candidate for reducing cardiac toxicity of anthracyclines is dexrazoxane. Dexrazoxane is an iron chelator which has proven efficacy in preclinical models to prevent long-term cardiotoxicity, protect myocardial mitochondria from genetic and functional lesions, reduce apoptosis and decrease mitochondrial remodeling15,16. It has a proven role in reducing cardiac toxicity in adults treated with anthracycline as shown in a Cochrane review17.

In children, data for safety and efficacy has taken a longer time to establish. In 2005 dexrazoxane was shown to reduce the levels of cardiac troponin release during doxorubicin infusion18. This was seen to be a surrogate marker of reduced cardiac injury by doxorubicin. In 2010 results were published indicating the long term efficacy of dexrazoxane at proctecting against cardiac dysfunction as measured by echocardiographic measurements in children over a median period of 8.7 years19. This randomized controlled trial of 205 children demonstrated that dexrazoxane had a long-term cardioprotective effect as measured by echocardiographic measurements of left ventricular structure and function. There was no adverse effect on relapse risk, frequency of secondary malignancy or survival in this cohort.

Pediatric Oncology Group Protocol POG 9404 was a randomised controlled trial enrolling patients with T cell acute lymphoblastic leukaemia and randomly assigning to treatment with or without dexrazoxane20. 5-year event-free survival did not differ between groups and there was no difference in toxicity. Measurements of fractional shortening, LV wall thickness and thickness-to-dimension ratio were worse in patients who did not receive dexrazoxane.

The safety of dexrazoxane was questioned when an article was published in 2007 claiming that dexrazoxane may contribute to an increased rate of secondary malignancy, particularly acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) when used in patients with Hodgkin lymphoma receiving combination chemotherapy21. This was the first time such a finding was reported in the literature and the statistical analysis which led to this conclusion was questioned and criticised# 22,23.

Despite this report being isolated and criticised, as a result of this publication the European Medicines Agency (EMA) recommended that dexrazoxane not be used in children or adolescents due to the possible increased risk of AML/MDS.

Since this time Seif et al. have published a report on a cohort of 15,532 patients receiving anthracycline, of which 1406 children received dexrazoxane. They demonstrate no difference in the rate of secondary AML24. In 2015 Chow et al. published the results of a pooled analysis of individual patient data treated in clinical trials for T cell acute lymphoblastic leukaemia/lymphoma and Hodgkin lymphoma where patients were randomly assigned to receive dexrazoxane or not. They found that overall mortality at 10 years did not differ by dexrazoxane group, second malignancy rates were not different between groups and there was no increase in relapse in patients receiving dexrazoxane25. The accompanying commentary questions the EMA decision and suggests re-evaluation26.

Dosing of dexrazoxane has been fairly consistent across studies at a dose ratio of 10:1 with doxorubicin19. Where other anthracyclines have been used the optimal ratio is less clear. The Children's Oncology Group (COG) has developed survivorship guidelines which utilise doxorubicin-equivalence factors for each of the commonly used anthracyclines27. The dose equivalences are shown below:

Doxorubicin Multiply dose x 1
Daunorubicin Multiply dose x 1
Epirubicin Multiply dose x 0.67
Idarubicin Multiply dose x 5
Mitoxantrone Multiply dose x 4

For the purposes of dosing dexrazoxane, the anthracycline dose should be multiplied by the appropriate figure and then a 10:1 ratio with dexrazoxane applied. Eg. A 10mg/m2 dose of mitoxantrone would require a 400mg/m2 dose of dexrazoxane (10mg/m2 x 4 x 10).

Some protocols use dexrazoxane with anthracycline only after a certain cumulative dose has been given. Currently the evidence for cardioprotection in children receiving anthracycline is for the use of dexrazoxane with every dose of anthracycline19 and delayed use of dexrazoxane is experimental.

In the treatment of some paediatric malignancies, long infusions of anthracycline are recommended. In this setting dexrazoxane is not able to be used, but physicians may, at their discretion, wish to alter protocols to reduce infusions to boluses in light of publications suggesting no difference in efficacy between infusion and bolus dosing for some diseases14.

#  The difference in secondary malignancy rate was not statistically significant by Fisher's exact test nor by time-to-event analysis.  It only became statistically significant (and then only for all secondary malignancies, not for AML/MDS)  when a Poisson regression model was used to adjust for race, age and sex despite no differences between race, age and sex being demonstrated between the groups.

Summary

Late cardiac morbidity and mortality is a significant contributor to late effects in patients who have received anthracycline-containing chemotherapy. There is no dose of anthracycline which is free of the risk of late effects but risk of morbidity is higher with higher cumulative doses, younger age at delivery, female sex and delivery of thoracic radiotherapy as part of treatment.

Dexrazoxane has been demonstrated to be safe, when used in a 10:1 ratio with doxorubicin equivalence. Its efficacy has been shown by surrogate markers, including echocardiographic measurements at 5 years and troponin release at administration but has not been demonstrated as yet to hard endpoints such as cardiac death and congestive heart failure. It is likely these data will not be available for another decade or more given the prolonged time-to-event for cardiac morbidity in this population.

Other causes of cardiac damage will not be mitigated with dexrazoxane. Undernutrition can be a contributor to loss of cardiac muscle and nutrition will need to continue to be addressed in its own right despite the use of dexrazoxane.

Dexrazoxane has a cost associated with it and its use needs to be considered in light of finite resources in the public health setting. Given the risk of significant cardiotoxicity is the highest for patients receiving high doses of anthracycline, young patients and those who will receive thoracic radiotherapy dexrazoxane is recommended for use in the following situations:

  1. Infants and children aged <5 years receiving anthracycline chemotherapy with an anticipated cumulative dose ≥ 250mg/m2* doxorubicin equivalence
  2. Older children and adolescents up to 19 years receiving anthracycline chemotherapy with an anticipated cumulative dose ≥ 300mg/m2* doxorubicin equivalence
  3. All children and adolescents up to 19 who are anticipated to receive thoracic radiotherapy to 30Gy* or higher who will also receive anthracyclines with an anticipated cumulative dose ≥ 250mg/m2
  4. All children and adolescents up to 19 who show cardiac dysfunction with an absolute drop in fractional shortening (FS) by ≥ 10% or FS < 28% where there are no specific treatment recommendations in their treatment protocol for this occurrence, or where the treating clinician deems that ongoing anthracycline is warranted despite cardiac dysfunction
  5. All children and adolescents enrolled on clinical trials where dexrazoxane is recommended or mandated as part of protocol

*Cutoffs are derived from COG survivorship guidelines and publications of groups with highest risk2,27

Cost is currently $640.26 per 500mg dose and, if used according to the above guidelines, the average cost per patient is approximately $5500. This is a fairly modest cost in the scheme of oncology treatment delivery and will apply to a small minority of patients only - perhaps 8-10%. The ongoing cost and use of dexrazoxane will continue to be collected and analysed. This guideline will also be formally reviewed after the results of Children's Oncology Group trial ALTE11C2 are available. This is a long term follow-up study of children who have received dexrazoxane on a number of clinical trials.

Disease Protocol Arm Doxorubicin (equiv.) dose Patients affected
Osteosarcoma EURAMOS/AOST0331 Standard 450mg/m2 All
Ewing sarcoma EuroEwing  All 360mg/m2 All 
Rhabdomyosarcoma ARST0532 (HR) All 375mg/m2 All 
Acute myeloid leukaemia AAML1031 All 492mg/m2 All 
Nephroblastoma AREN0534 Regimen I 250mg/m2 < 5 years 

See also additional notes for PTAC

References

  1. Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med. 1991 Mar 21;324(12):808-15
  2. Mulrooney DA, Yeazel MW, Kawashima T et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009 Dec 8;339:b4606
  3. Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med. 1995 Jun 29;332(26):1738-43.
  4. Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voûte PA. Anthracycline-induced clinical heart failure in a cohort of 607 children: Long-term follow-up study. J Clin Oncol. 2001 Jan 1;19(1):191-6
  5. Trachtenberg BH, Landy DC, Franco VI, Henkel JM, Pearson EJ, Miller TL, Lipshultz SE. Anthracycline-associated cardiotoxicity in survivors of childhood cancer. Pediatr Cardiol. 2011 Mar;32(3):342-53
  6. Leger K, Slone T, Lemler M et al. Subclinical cardiotoxicity in childhood cancer survivors exposed to very low dose anthracycline therapy. Pediatr Blood Cancer. 2015 Jan;62(1):123-7
  7. Chow EJ, Chen Y, Kremer LC et al. Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol. 2015 Feb 10;33(5):394-402
  8. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic Progressive Cardiac Dysfunction Years After Doxorubicin Therapy for Childhood Acute Lymphoblastic Leukemia. J Clin Oncol 2005 Apr 20;23(12):2629-36
  9. Lipshultz SE, Rifai N, Sallan SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 1997;96:2641-2648
  10. Kremer LC, van Dalen EC, Offringa M, et al: Anthracycline-induced clinical heart failure in a cohort of 607 children: Long-term follow-up study. J Clin Oncol 19:191-196, 2001
  11. Green DM, Grigoriev YA, Nan B, et al: Congestive heart failure after treatment for Wilm's tumor: A report from the national Wilm's tumor study group. J Clin Oncol 19:1926-1934, 2001
  12. 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;19:3163-3172
  13. Pritchard-Jones K, Bergeron C, de Camargo B et al. Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial. Lancet. 2015 Sep 19;386(9999):1156-64.
  14. Lipshultz SE, Miller TL, Lipsitz SR et al. Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes. Pediatrics. 2012 Dec;130(6):1003-11
  15. Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol 2005;131:561-78
  16. Lebrecht D, Geist A, Ketelsen UP, Haberstroh J, Setzer B, Walker UA. Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. Br J Pharmacol 2007;151:771-78
  17. van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database of Systematic Reviews, Issue 6, Art. No.: CD003917
  18. Lipshultz SE, Rafai 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 Jul 8;351(2):145-53
  19. Lipshultz SE, Scully RE, Sallan SE, et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 2010; 11:950-61
  20. Asselin BL, Devidas M, Chen L et al. Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404. J Clin Oncol. 2016 Mar 10;34(8):854-62
  21. Tebbi CK, London WB, Friedman D et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol. 2007 Feb 10;25(5):493-500.
  22. Lipshultz SE, Lipsitz SR, Orav EJ. Dexrazoxane-associated risk for secondary malignancies in pediatric Hodgkin's disease: a claim without compelling evidence. J Clin Oncol. 2007 Jul 20;25(21):3179
  23. Hellmann K. Dexrazoxane-associated risk for secondary malignancies in pediatric Hodgkin's disease: a claim without evidence. J Clin Oncol. 2007 Oct 10;25(29):4689-90
  24. Seif AE, Walker DM, Li Y et al. Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients. Pediatr Blood Cancer. 2015 Apr;62(4):704-9
  25. Chow EJ, Asselin BL, Schwartz CL et al. Late Mortality After Dexrazoxane Treatment: A Report From the Children's Oncology Group. J Clin Oncol. 2015 Aug 20;33(24):2639-45
  26. Kremer LC, van Dalen EC. Dexrazoxane in Children With Cancer: From Evidence to Practice. J Clin Oncol. 2015 Aug 20;33(24):2594-6
  27. Children's Oncology Group. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer. Version 4.0 - October 2013. www.survivorshipguidelines.org/pdf/LTFUGuidelines_40.pdf Accessed 24/11/2016

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Document Control

  • Date last published: 22 January 2018
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network
  • Owner: Andrew Dodgshun
  • Review frequency: 2 years

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