Detection of subclinical cardiotoxicity in sarcoma patients receiving continuous doxorubicin infusion or pre-treatment with dexrazoxane before bolus doxorubicin

Jieli Li, Hui-Ming Chang, Jose Banchs, Dejka M Araujo, Saamir A Hassan, Elizabeth A Wagar, Edward T H Yeh, Qing H Meng, Jieli Li, Hui-Ming Chang, Jose Banchs, Dejka M Araujo, Saamir A Hassan, Elizabeth A Wagar, Edward T H Yeh, Qing H Meng

Abstract

Background: Continuous infusion of doxorubicin or dexrazoxane pre-treatment prior to bolus doxorubicin are proven strategies to protect against doxorubicin-induced cardiotoxicity. Recently, global longitudinal peak systolic strain (GLS) measured with speckle tracking echocardiography (STE) and high-sensitivity troponin T (hs-TnT) have been validated as sensitive indicators of doxorubicin-induced cardiotoxicity. Here, we asked whether changes in hs-TnT and/or GLS can be detected in patients who were treated with continuous infusion of doxorubicin or pre-treated with dexrazoxane followed by bolus doxorubicin.

Methods: Twenty-nine patients with newly diagnosed sarcoma were assigned to receive either 72-h doxorubicin infusion or dexrazoxane pre-treatment before bolus doxorubicin. Eight patients received dexrazoxane pre-treatment; eleven patients received continuous doxorubicin infusion; ten patients crossed over from continuous infusion to dexrazoxane. Bloods were collected for hs-TnT at baseline, 24 h or 72 h after initiation of doxorubicin treatment in each chemotherapy cycle. All blood samples were assayed in batch using hs-TnT kit from Roche diagnostics. 2D Echo and STE were performed before doxorubicin, after cycle 3, and at the end of chemotherapy.

Results: Seven patients in the cross-over group have at least one hs-TnT measurement between 5 ng/L to 10 ng/L during and after chemotherapy. Ten patients have at least one hs-TnT measurement above 10 ng/ml during and after chemotherapy (six in dexrazoxane group, three in continuous infusion group, one in cross-over group). The average hs-TnT level increases with each additional cycle of doxorubicin treatment. Eight patients had a more than 5% reduction in LVEF at the end of chemotherapy (four in dexrazoxane group, three in continuous infusion group, and one in cross-over group). Four out of these eight patients had a change of GLS by more than 15% (three in the dexrazoxane group).

Conclusion: Elevation in hs-TnT levels were observed in more than 59% of patients who had received either continuous doxorubicin infusion or dexrazoxane pre-treatment before bolus doxorubicin. However, changes in LVEF and GLS were less frequently observed. Thus, continuous doxorubicin infusion or dexrazoxane pre-treatment do not completely ameliorate subclinical doxorubicin-induced cardiotoxicity as detected by more sensitive techniques.

Keywords: Cardiotoxicity; Continuous doxorubicin infusion; Dexrazoxane; Global longitudinal strain; High sensitivity troponin T.

Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

© The Author(s). 2020.

Figures

Fig. 1
Fig. 1
Time-line of hs-TnT results with doxorubicin continuous infusion or dexrazoxane pre-treatment. a Absolute value of hs-TnT with each chemotherapy cycle b Fold change of baseline of hs-TnT with each chemotherapy cycle. C1: cycle 1; C1B: cycle 1 baseline

References

    1. Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1. J Am Coll Cardiol. 2017;70(20):2536–2551. doi: 10.1016/j.jacc.2017.09.1096.
    1. Cardinale D, Colombo A, Lamantia G, Colombo N, Civelli M, De Giacomi G, Rubino M, Veglia F, Fiorentini C, Cipolla CM. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010;55(3):213–220. doi: 10.1016/j.jacc.2009.03.095.
    1. Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G, Civelli M, Peccatori F, Martinelli G, Fiorentini C, Cipolla CM. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109(22):2749–2754. doi: 10.1161/.
    1. Cardinale D, Sandri MT, Martinoni A, Tricca A, Civelli M, Lamantia G, Cinieri S, Martinelli G, Cipolla CM, Fiorentini C. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol. 2000;36(2):517–522. doi: 10.1016/S0735-1097(00)00748-8.
    1. Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol. 2008;26(22):3777–3784. doi: 10.1200/JCO.2007.14.9401.
    1. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56(2):185–229. doi: 10.1124/pr.56.2.6.
    1. Ewer M, Yeh ET. Cancer and the heart: BC Decker. 2006.
    1. Lum BL, Svec JM, Torti FM. Doxorubicin: alteration of dose scheduling as a means of reducing cardiotoxicity. Drug Intell Clin Pharm. 1985;19(4):259–264. doi: 10.1177/106002808501900403.
    1. Lipshultz SE, Miller TL, Lipsitz SR, Neuberg DS, Dahlberg SE, Colan SD, Silverman LB, Henkel JM, Franco VI, Cushman LL, Asselin BL, Clavell LA, Athale U, Michon B, Laverdiere C, Schorin MA, Larsen E, Usmani N, Sallan SE. Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes. Pediatrics. 2012;130(6):1003–1011. doi: 10.1542/peds.2012-0727.
    1. Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984;226(4673):466–468. doi: 10.1126/science.6093249.
    1. Doroshow JH. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 1983;43(2):460–472.
    1. Hasinoff BB. Chemistry of dexrazoxane and analogues. Semin Oncol. 1998;25(4 Suppl 10):3–9.
    1. Swain SM. Adult multicenter trials using dexrazoxane to protect against cardiac toxicity. Semin Oncol. 1998;25(4 Suppl 10):43–47.
    1. Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, Yeh ET. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012;18(11):1639–1642. doi: 10.1038/nm.2919.
    1. Vavrova A, Jansova H, Mackova E, Machacek M, Haskova P, Tichotova L, Sterba M, Simunek T. Catalytic inhibitors of topoisomerase II differently modulate the toxicity of anthracyclines in cardiac and cancer cells. PLoS One. 2013;8(10):e76676. doi: 10.1371/journal.pone.0076676.
    1. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869–2879. doi: 10.1002/cncr.11407.
    1. Asselin BL, Devidas M, Chen L, Franco VI, Pullen J, Borowitz MJ, Hutchison RE, Ravindranath Y, Armenian SH, Camitta BM, Lipshultz SE. 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;34(8):854–862. doi: 10.1200/JCO.2015.60.8851.
    1. Lipshultz SE, Scully RE, Lipsitz SR, Sallan SE, Silverman LB, Miller TL, Barry EV, Asselin BL, Athale U, Clavell LA, Larsen E, Moghrabi A, Samson Y, Michon B, Schorin MA, Cohen HJ, Neuberg DS, Orav EJ, Colan SD. 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(10):950–961. doi: 10.1016/S1470-2045(10)70204-7.
    1. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Jr, Ganiats TG, Holmes DR, Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 AHA/ACC guideline for the Management of Patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014;64(24):e139–e228. doi: 10.1016/j.jacc.2014.09.017.
    1. Brush JE, Jr, Kaul S, Krumholz HM. Troponin testing for clinicians. J Am Coll Cardiol. 2016;68(21):2365–2375. doi: 10.1016/j.jacc.2016.08.066.
    1. Ky B, Putt M, Sawaya H, French B, Januzzi JL, Jr, Sebag IA, Plana JC, Cohen V, Banchs J, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer-Crosbie M. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol. 2014;63(8):809–816. doi: 10.1016/j.jacc.2013.10.061.
    1. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, Gosavi S, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer-Crosbie M. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol. 2011;107(9):1375–1380. doi: 10.1016/j.amjcard.2011.01.006.
    1. Kitayama H, Kondo T, Sugiyama J, Kurimoto K, Nishino Y, Kawada M, Hirayama M, Tsuji Y. High-sensitive troponin T assay can predict anthracycline- and trastuzumab-induced cardiotoxicity in breast cancer patients. Breast Cancer. 2017;24(6):774–782. doi: 10.1007/s12282-017-0778-8.
    1. Roziakova L, Bojtarova E, Mistrik M, Dubrava J, Gergel J, Lenkova N, Mladosievicova B. Serial measurements of cardiac biomarkers in patients after allogeneic hematopoietic stem cell transplantation. J Exp Clin Cancer Res. 2012;31:13. doi: 10.1186/1756-9966-31-13.
    1. Pourier MS, Kapusta L, van Gennip A, Bokkerink JP, Loonen J, Bellersen L, Mavinkurve-Groothuis AM. Values of high sensitive troponin T in long-term survivors of childhood cancer treated with anthracyclines. Clin Chim Acta. 2015;441:29–32. doi: 10.1016/j.cca.2014.12.011.
    1. Kang Y, Xu X, Cheng L, Li L, Sun M, Chen H, Pan C, Shu X. Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy. Eur J Heart Fail. 2014;16(3):300–308. doi: 10.1002/ejhf.8.
    1. Sandoval Y, Jaffe AS. Using high-sensitivity cardiac troponin T for acute cardiac care. Am J Med. 2017;130(12):1358–65 e1. doi: 10.1016/j.amjmed.2017.07.033.
    1. Herman EH, Zhang J, Lipshultz SE, Rifai N, Chadwick D, Takeda K, Yu ZX, Ferrans VJ. Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol. 1999;17(7):2237–2243. doi: 10.1200/JCO.1999.17.7.2237.
    1. Kavsak PA, Andruchow JE, McRae AD, Worster A. Profile of Roche's Elecsys troponin T gen 5 STAT blood test (a high-sensitivity cardiac troponin assay) for diagnosing myocardial infarction in the emergency department. Expert Rev Mol Diagn. 2018;18(6):481–489. doi: 10.1080/14737159.2018.1476141.

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