Cancer Chemotherapy and Pharmacology

, Volume 80, Issue 4, pp 787–798 | Cite as

Cardiac safety profile of patients receiving high cumulative doses of pegylated-liposomal doxorubicin: use of left ventricular ejection fraction is of unproven value

  • Keith M. SkubitzEmail author
  • Anne H. Blaes
  • Suma H. Konety
  • Gary S. Francis
Original Article



One of the great conundrums for both oncologists and cardiologists is how to best monitor the potential and actual cardiotoxicity of doxorubicin. Pegylated-liposomal doxorubicin (PLD) has a safer cardiotoxicity profile than bolus administration of doxorubicin. Although ejection fraction (EF) is commonly performed to monitor doxorubicin-induced cardiotoxicity, evidence for its predictive utility is limited. We examined the incidence of doxorubicin-induced heart failure (HF) in patients who received a large cumulative dose of doxorubicin as PLD and its relation to EF and HF.


A retrospective chart review of patients who received a large cumulative dose of PLD, sometimes after previous free doxorubicin treatment, was performed to examine the incidence of doxorubicin-induced heart failure (HF) and its relation to EF and development of HF.


No definite doxorubicin-induced clinical HF was observed among 56 patients (median age 54; 15–93) who received a cumulative doxorubicin dose (free + PLD) of >450 mg/m2. Of these, 49 received >500 mg/m2, 28 > 700 mg/m2, 19 > 800 mg/m2, 14 > 1000 mg/m2, and 5 > 1400 mg/m2. The EF varied greatly over time in some patients treated with PLD in the absence of symptoms or signs of heart failure, and was not particularly useful in making decisions regarding further dosing.


Pegylated-liposomal doxorubicin was associated with a low risk of doxorubicin-induced HF in a retrospective cohort of patients receiving large cumulative doses of doxorubicin and long-term follow-up. EF did not predict doxorubicin-induced cardiotoxicity in our cohort of adult patients receiving PLD. Given the lack of prognostic clarity regarding modest EF changes, regular EF monitoring may not be warranted, at least when PLD is used in adults. Modest changes in EF should probably not be used to limit a patient’s access to PLD, but may warrant cardiology consultation for long-term follow-up after completion of therapy.


Anthracycline Cardiotoxicity Cardio-oncology Ejection fraction Heart failure Pegylated-liposomal doxorubicin 


Compliance and ethical standards


This study received no funding.

Conflict of interest

Dr. Skubitz has received research funding from Johnson & Johnson or its subsidiaries and has owned publicly traded stock in JNJ in the past. The other authors have no potential conflict.

Ethical standards

This study was approved by the University of Minnesota IRB and was performed in accordance with the ethical standards of the institutional IRB and the 1964 Helsinki declaration and its later amendments.

Human and animal rights

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was not obtained, per the approval of the University of Minnesota IRB, as it was a retrospective study, no identifying information is presented, and many of the patients are no longer living.

Supplementary material

280_2017_3420_MOESM1_ESM.docx (43 kb)
Supplementary material 1 (DOCX 43 kb)


  1. 1.
    Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91(5):710–717CrossRefGoogle Scholar
  2. 2.
    Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97(11):2869–2879. doi: 10.1002/cncr.11407 CrossRefPubMedGoogle Scholar
  3. 3.
    Stevenson LW, Perloff JK (1989) The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA 261(6):884–888CrossRefPubMedGoogle Scholar
  4. 4.
    Legha SS, Benjamin RS, Mackay B, Ewer M, Wallace S, Valdivieso M, Rasmussen SL, Blumenschein GR, Freireich EJ (1982) Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96(2):133–139CrossRefPubMedGoogle Scholar
  5. 5.
    Bielack SS, Erttmann R, Winkler K, Landbeck G (1989) Doxorubicin: effect of different schedules on toxicity and anti-tumor efficacy. Eur J Cancer Clin Oncol 25(5):873–882CrossRefPubMedGoogle Scholar
  6. 6.
    Lokich J, Bothe A, Zipoli T, Green R, Sonneborn H, Paul S, Philips D (1983) Constant infusion schedule for adriamycin: a phase I-II clinical trial of a 30-day schedule by ambulatory pump delivery system. J Clin Oncol 1(1):24–28CrossRefPubMedGoogle Scholar
  7. 7.
    Samuels BL, Vogelzang NJ, Ruane M, Simon MA (1987) Continuous venous infusion of doxorubicin in advanced sarcomas. Cancer Treat Rep 71(10):971–972PubMedGoogle Scholar
  8. 8.
    Shapira J, Gotfried M, Lishner M, Ravid M (1990) Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation. Cancer 65(4):870–873CrossRefPubMedGoogle Scholar
  9. 9.
    Hamdan H, Savage PD, Thompson RC, Skubitz KM (1992) A phase I study of ambulatory continuous infusion chemotherapy with cyclophosphamide, doxorubicin, and dacarbazine, (caCAD) for soft tissue sarcomas. J Infus Chemother 2:97–105Google Scholar
  10. 10.
    Zalupski M, Metch B, Balcerzak S, Fletcher WS, Chapman R, Bonnet JD, Weiss GR, Ryan J, Benjamin RS, Baker LH (1991) Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst 83(13):926–932CrossRefPubMedGoogle Scholar
  11. 11.
    Alberts DS, Muggia FM, Carmichael J, Winer EP, Jahanzeb M, Venook AP, Skubitz KM, Rivera E, Sparano JA, DiBella NJ, Stewart SJ, Kavanagh JJ, Gabizon AA (2004) Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials. Semin Oncol 31(6 Suppl 13):53–90CrossRefPubMedGoogle Scholar
  12. 12.
    Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang A, Barenholz Y (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54(4):987–992PubMedGoogle Scholar
  13. 13.
    Northfelt DW, Martin FJ, Working P, Volberding PA, Russell J, Newman M, Amantea MA, Kaplan LD (1996) Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi’s sarcoma. J Clin Pharmacol 36(1):55–63CrossRefPubMedGoogle Scholar
  14. 14.
    Working PK, Dayan AD (1996) Pharmacological-toxicological expert report. CAELYX. (Stealth liposomal doxorubicin HCl). Hum Exp Toxicol 15(9):751–785PubMedGoogle Scholar
  15. 15.
    Working PK, Newman MS, Sullivan T, Yarrington J (1999) Reduction of the cardiotoxicity of doxorubicin in rabbits and dogs by encapsulation in long-circulating, pegylated liposomes. J Pharmacol Exp Ther 289(2):1128–1133PubMedGoogle Scholar
  16. 16.
    Berry G, Billingham M, Alderman E, Richardson P, Torti F, Lum B, Patek A, Martin FJ (1998) The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s sarcoma patients treated with pegylated liposomal doxorubicin. Ann Oncol 9(7):711–716CrossRefPubMedGoogle Scholar
  17. 17.
    O’Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C, Group CBCS (2004) Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 15(3):440–449CrossRefPubMedGoogle Scholar
  18. 18.
    Skubitz KM (2002) Phase II trial of pegylated-liposomal doxorubicin (Doxil) in mesothelioma. Cancer Investig 20(5–6):693–699CrossRefGoogle Scholar
  19. 19.
    Skubitz KM (2003) Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Cancer Investig 21(2):167–176CrossRefGoogle Scholar
  20. 20.
    Rayson D, Suter TM, Jackisch C, van der Vegt S, Bermejo B, van den Bosch J, Vivanco GL, van Gent AM, Wildiers H, Torres A, Provencher L, Temizkan M, Chirgwin J, Canon JL, Ferrandina G, Srinivasan S, Zhang L, Richel DJ (2012) Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial. Ann Oncol 23(7):1780–1788. doi: 10.1093/annonc/mdr519 CrossRefPubMedGoogle Scholar
  21. 21.
    Gill SE, Savage K, Wysham WZ, Blackhurst DW, Winter WE, Puls LE (2013) Continuing routine cardiac surveillance in long-term use of pegylated liposomal doxorubicin: is it necessary? Gynecol Oncol 129(3):544–547. doi: 10.1016/j.ygyno.2013.03.012 CrossRefPubMedGoogle Scholar
  22. 22.
    Kesterson JP, Odunsi K, Lele S (2010) High cumulative doses of pegylated liposomal doxorubicin are not associated with cardiac toxicity in patients with gynecologic malignancies. Chemotherapy 56(2):108–111. doi: 10.1159/000312644 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Safra T, Muggia F, Jeffers S, Tsao-Wei DD, Groshen S, Lyass O, Henderson R, Berry G, Gabizon A (2000) Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 11(8):1029–1033CrossRefPubMedGoogle Scholar
  24. 24.
    Kushnir CL, Angarita AM, Havrilesky LJ, Thompson S, Spahlinger D, Sinno AK, Tanner EJ, Secord AA, Roche KL, Stone RL, Fader AN (2015) Selective cardiac surveillance in patients with gynecologic cancer undergoing treatment with pegylated liposomal doxorubicin (PLD). Gynecol Oncol. doi: 10.1016/j.ygyno.2015.02.020 PubMedGoogle Scholar
  25. 25.
    Brana I, Tabernero J (2010) Cardiotoxicity. Ann Oncol 21(Suppl 7):vii173–vii179. doi: 10.1093/annonc/mdq295 PubMedGoogle Scholar
  26. 26.
    Skubitz KM (2002) Phase II trial of pegylated-liposomal doxorubicin (Doxil) in renal cell cancer. Investig New Drugs 20(1):101–104CrossRefGoogle Scholar
  27. 27.
    Bosch X, Rovira M, Sitges M, Domenech A, Ortiz-Perez JT, de Caralt TM, Morales-Ruiz M, Perea RJ, Monzo M, Esteve J (2013) Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 61(23):2355–2362. doi: 10.1016/j.jacc.2013.02.072 CrossRefPubMedGoogle Scholar
  28. 28.
    Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, Civelli M, Lamantia G, Colombo N, Curigliano G, Fiorentini C, Cipolla CM (2015) Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 131(22):1981–1988. doi: 10.1161/CIRCULATIONAHA.114.013777 CrossRefPubMedGoogle Scholar
  29. 29.
    Uyar D, Kulp B, Peterson G, Zanotti K, Markman M, Belinson J (2004) Cardiac safety profile of prolonged (> or =6 cycles) pegylated liposomal doxorubicin administration in patients with gynecologic malignancies. Gynecol Oncol 94(1):147–151. doi: 10.1016/j.ygyno.2004.03.024 CrossRefPubMedGoogle Scholar
  30. 30.
    Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P, Stovall M, Donaldson SS, Green DM, Sklar CA, Robison LL, Leisenring WM (2009) Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 339:b4606. doi: 10.1136/bmj.b4606 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Visscher H, Ross CJ, Rassekh SR, Barhdadi A, Dube MP, Al-Saloos H, Sandor GS, Caron HN, van Dalen EC, Kremer LC, van der Pal HJ, Brown AM, Rogers PC, Phillips MS, Rieder MJ, Carleton BC, Hayden MR, Canadian Pharmacogenomics Network for Drug Safety C (2012) Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J Clin Oncol 30(13):1422–1428. doi: 10.1200/JCO.2010.34.3467 CrossRefPubMedGoogle Scholar
  32. 32.
    Altena R, Perik PJ, van Veldhuisen DJ, de Vries EG, Gietema JA (2009) Cardiovascular toxicity caused by cancer treatment: strategies for early detection. Lancet Oncol 10(4):391–399. doi: 10.1016/S1470-2045(09)70042-7 CrossRefPubMedGoogle Scholar
  33. 33.
    Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y, Early Breast Cancer Trialists’ Collaborative G (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366(9503):2087–2106. doi: 10.1016/S0140-6736(05)67887-7 CrossRefPubMedGoogle Scholar
  34. 34.
    Ng R, Better N, Green MD (2006) Anticancer agents and cardiotoxicity. Semin Oncol 33(1):2–14. doi: 10.1053/j.seminoncol.2005.11.001 CrossRefPubMedGoogle Scholar
  35. 35.
    Thavendiranathan P, Abdel-Qadir H, Fischer HD, Camacho X, Amir E, Austin PC, Lee DS (2016) Breast cancer therapy-related cardiac dysfunction in adult women treated in routine clinical practice: a population-based cohort study. J Clin Oncol. doi: 10.1200/JCO.2015.65.1505 Google Scholar
  36. 36.
    Asselin BL, Devidas M, Chen L, Franco VI, Pullen J, Borowitz MJ, Hutchison RE, Ravindranath Y, Armenian SH, Camitta BM, Lipshultz SE (2015) 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. doi: 10.1200/JCO.2015.60.8851 Google Scholar
  37. 37.
    Galal A, El-Bakly WM, Al Haleem EN, El-Demerdash E (2015) Selective A adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity. Cancer Chemother Pharmacol. doi: 10.1007/s00280-015-2937-y PubMedGoogle Scholar
  38. 38.
    Shapiro CL, Ervin T, Welles L, Azarnia N, Keating J, Hayes DF (1999) Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer. TLC D-99 Study Group. J Clin Oncol 17(5):1435–1441CrossRefPubMedGoogle Scholar
  39. 39.
    Thavendiranathan P, Grant AD, Negishi T, Plana JC, Popovic ZB, Marwick TH (2013) Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy. J Am Coll Cardiol 61(1):77–84. doi: 10.1016/j.jacc.2012.09.035 CrossRefPubMedGoogle Scholar
  40. 40.
    Otterstad JE (2002) Measuring left ventricular volume and ejection fraction with the biplane Simpson’s method. Heart 88(6):559–560CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Jensen MM, Schmidt U, Huang C, Zerahn B (2014) Gated tomographic radionuclide angiography using cadmium-zinc-telluride detector gamma camera; comparison to traditional gamma cameras. J Nucl Cardiol 21(2):384–396. doi: 10.1007/s12350-013-9844-6 CrossRefPubMedGoogle Scholar
  42. 42.
    Jensen MM, Haase C, Zerahn B (2015) Interstudy repeatability of left and right ventricular volume estimations by serial-gated tomographic radionuclide angiographies using a cadmium-zinc-telluride detector gamma camera. Clin Physiol Funct Imaging 35(6):418–424. doi: 10.1111/cpf.12178 CrossRefPubMedGoogle Scholar
  43. 43.
    Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, Criscitiello C, Goldhirsch A, Cipolla C, Roila F, Group EGW (2012) Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 23(Suppl 7):vii155–vii166. doi: 10.1093/annonc/mds293 CrossRefPubMedGoogle Scholar
  44. 44.
    Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, Ganame J, Sebag IA, Agler DA, Badano LP, Banchs J, Cardinale D, Carver J, Cerqueira M, DeCara JM, Edvardsen T, Flamm SD, Force T, Griffin BP, Jerusalem G, Liu JE, Magalhaes A, Marwick T, Sanchez LY, Sicari R, Villarraga HR, Lancellotti P (2014) Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 15(10):1063–1093. doi: 10.1093/ehjci/jeu192 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Tang WH, Thomas S, Kalaycio M, Sobecks R, Andresen S, Jarvis J, Rybicki L, Pohlman B, Francis GS, Bolwell BJ (2004) Clinical outcomes of patients with impaired left ventricular ejection fraction undergoing autologous bone marrow transplantation: can we safely transplant patients with impaired ejection fraction? Bone Marrow Transpl 34(7):603–607. doi: 10.1038/sj.bmt.1704610 CrossRefGoogle Scholar
  46. 46.
    Hurley P, Konety S, Cao Q, Weisdorf D, Blaes A (2015) Hematopoietic stem cell transplantation in patients with systolic dysfunction: can it be done? Biol Blood Marrow Transpl 21(2):300–304. doi: 10.1016/j.bbmt.2014.10.011 CrossRefGoogle Scholar
  47. 47.
    Chavez-MacGregor M, Niu J, Zhang N, Elting LS, Smith BD, Banchs J, Hortobagyi GN, Giordano SH (2015) Cardiac monitoring during adjuvant trastuzumab-based chemotherapy among older patients with breast cancer. J Clin Oncol 33(19):2176–2183. doi: 10.1200/JCO.2014.58.9465 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Burdick J, Berridge B, Coatney R (2015) Strain echocardiography combined with pharmacological stress test for early detection of anthracycline induced cardiomyopathy. J Pharmacol Toxicol Methods 73:15–20. doi: 10.1016/j.vascn.2015.02.004 CrossRefPubMedGoogle Scholar
  49. 49.
    Christian JB, Finkle JK, Ky B, Douglas PS, Gutstein DE, Hockings PD, Lainee P, Lenihan DJ, Mason JW, Sager PT, Todaro TG, Hicks KA, Kane RC, Ko HS, Lindenfeld J, Michelson EL, Milligan J, Munley JY, Raichlen JS, Shahlaee A, Strnadova C, Ye B, Turner JR (2012) Cardiac imaging approaches to evaluate drug-induced myocardial dysfunction. Am Heart J 164(6):846–855. doi: 10.1016/j.ahj.2012.09.001 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Burridge PW, Li YF, Matsa E, Wu H, Ong SG, Sharma A, Holmstrom A, Chang AC, Coronado MJ, Ebert AD, Knowles JW, Telli ML, Witteles RM, Blau HM, Bernstein D, Altman RB, Wu JC (2016) Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med 22(5):547–556. doi: 10.1038/nm.4087 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Department of MedicineThe University of Minnesota Medical SchoolMinneapolisUSA
  2. 2.Masonic Cancer Center, University of Minnesota Medical SchoolMinneapolisUSA

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