Skip to main content

Advertisement

SpringerLink
Log in

Replacement of conventional doxorubicin by pegylated liposomal doxorubicin is a safe and effective alternative in the treatment of non-Hodgkin's lymphoma patients with cardiac risk factors

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Anthracyclines are a major component in the therapy of non-Hodgkin's lymphoma. However, due to their cardiac toxicity potential, curative and palliative treatment is often limited in patients with preexisting cardiac dysfunction. Liposomal doxorubicin formulations have been described to be less cardiotoxic than conventional doxorubicin. In the current study, we analyzed the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) as constituent of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen replacing conventional doxorubicin in 21 patients with impaired cardiac left ventricular ejection fraction or preexisting cardiac risk factors and established diagnosis of diffuse large B cell lymphoma (n = 15), mantle cell lymphoma (n = 3), follicular lymphoma (n = 1), and T cell lymphoma (n = 2). Overall and complete response rate were 85% and 40%, respectively. Event-free survival and overall survival after 2 years were 58%. One lethal event of acute cardiac death occurred during the first cycle in a patient with transposition of the big arteries, atrial flutter, and mitral valve regurgitation. In the remaining 20 patients, no deterioration of myocardial function was observed in echocardiography performed before and after treatment. Seven cases of grade III–IV hematological toxicity were observed as well as four episodes of neutropenic fever leading to hospitalization. No infection-related death occurred. However, 25% of patients developed a hand–foot syndrome (HFS) leading to discontinuation of treatment. Importantly, the incidence of HFS increased considerably when PLD doses of 15 mg/m2/week were exceeded. We conclude that replacing conventional doxorubicin with PLD in polychemotherapy regimens such as CHOP is an efficient alternative in the treatment of patients with preexisting cardiac dysfunction. However, we recommend that PLD dose should not exceed 15 mg/m2/week. The rationale for the use of non-pegylated liposomal doxorubicin formulations should be evaluated in further studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Antón A, Ruiz A, Seguí MA, Calvo L, Muñoz M, Lao J, Sancho F, Fernández L (2009) Phase I clinical trial of liposomal-encapsulated doxorubicin citrate and docetaxel, associated with trastuzumab, as neo-adjuvant treatment in stages II and IIIA, HER2-overexpressing breast cancer patients. GEICAM 2003–03 study. Ann Oncol 20:454–459, Epub 2008 Dec 11

    Article  PubMed  Google Scholar 

  2. Antón A, Ruiz A, Plazaola A, Calvo L, Seguí MA, Santaballa A, Muñoz M, Sánchez P, Miguel A, Carrasco E, Lao J, Camps J, Alfaro J, Antolín S, Cámara MC (2010) Phase II clinical trial of liposomal-encapsulated doxorubicin citrate and docetaxel, associated with trastuzumab, as neoadjuvant treatment in stages II and IIIA HER2-overexpressing breast cancer patients. GEICAM 2003–03 study. Ann Oncol 22:74–79

    Article  PubMed  Google Scholar 

  3. Baack BR, Burgdorf WH (1991) Chemotherapy-induced acral erythema. J Am Acad Dermatol 24:457–461

    Article  PubMed  CAS  Google Scholar 

  4. Beard JS, Smith KJ, Skelton HG (1993) Combination chemotherapy with 5-fluorouracil, folinic acid, and alpha-interferon producing histologic features of graft-versus-host disease. J Am Acad Dermatol 29:325–330

    Article  PubMed  CAS  Google Scholar 

  5. Brusamolino E, Rusconi C, Montalbetti L, Gargantini L, Uziel L, Pinotti G, Fava S, Rigacci L, Pagnucco G, Pascutto C, Morra E, Lazzarino M, 4 (2006) Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity. Haematologica 91:496–502, Epub 2006 Mar 15

    PubMed  CAS  Google Scholar 

  6. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-López A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP (1999) Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17(4):1244

    PubMed  CAS  Google Scholar 

  7. Coiffier B, Lepage E, Briere J et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242

    Article  PubMed  CAS  Google Scholar 

  8. Coleman RE, Biganzoli L, Canney P et al (2006) A randomised phase II study of two different schedules of pegylated liposomal doxorubicin in metastatic breast cancer (EORTC-10993). Eur J Cancer 42:882–887

    Article  PubMed  CAS  Google Scholar 

  9. de Nigris F, Rienzo M, Schiano C, Fiorito C, Casamassimi A, Napoli C (2008) Prominent cardioprotective effects of third generation beta blocker nebivolol against anthracycline-induced cardiotoxicity using the model of isolated perfused rat heart. Eur J Cancer 44(3):334–340

    Article  PubMed  Google Scholar 

  10. Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57(7):727–741

    Article  PubMed  CAS  Google Scholar 

  11. Gimeno E, Sánchez-González B, Alvarez-Larrán A, Pedro C, Abella E, Comín J, Saumell S, García-Pallarols F, Gómez M, Besses C, Salar A (2011) Intermediate dose of nonpegylated liposomal doxorubicin combination (R-CMyOP) as first line chemotherapy for frail elderly patients with aggressive lymphoma. Leuk Res 35:358–362

    Article  PubMed  CAS  Google Scholar 

  12. Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E, TLC D-99 Study Group (2002) Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 94(1):25–36

    Article  PubMed  CAS  Google Scholar 

  13. Heintel D, Skrabs C, Hauswirth A, Eigenberger K, Einberger C, Raderer M, Sperr WR, Knöbl P, Müllauer L, Uffmann M, Dieckmann K, Gaiger A, Jäger U (2010) Nonpegylated liposomal doxorubicin is highly active in patients with B and T/NK cell lymphomas with cardiac comorbidity or higher age. Ann Hematol 89(2):163–169

    Article  PubMed  CAS  Google Scholar 

  14. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT, St John Sutton M, Stewart W, 2 (2006) American Society of Echocardiography's Nomenclature and Standards Committee; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society of Cardiology. Recommendations for chamber quantification. Eur J Echocardiogr 7:79–108

    Article  PubMed  Google Scholar 

  15. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA (1973) A clinicopathologic analysis of Adriamycin cardiotoxicity. Cancer 32:302–314

    Article  PubMed  CAS  Google Scholar 

  16. Lorusso D, Naldini A, Testa A, D'Agostino G, Scambia G, Ferrandina G (2004) Phase II study of pegylated liposomal doxorubicin in heavily pretreated epithelial ovarian cancer patients. May a new treatment schedule improve toxicity profile? Oncology 67:243–249

    Article  PubMed  CAS  Google Scholar 

  17. Nagore E, Insa A, Sanmartin O (2000) Antineoplastic therapy-induced palmar plantar erythrodysesthesia (‘hand-foot’) syndrome. Incidence, recognition and management. Am J Clin Dermatol 1:225–234

    Article  PubMed  CAS  Google Scholar 

  18. 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 (2004) CAELYX Breast Cancer Study Group. 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):440–449

    Article  PubMed  Google Scholar 

  19. Parr MJ, Masin D, Cullis PR, Bally MB (1997) Accumulation of liposomal lipid and encapsulated doxorubicin in murine Lewis lung carcinoma: the lack of beneficial effects by coating liposomes with poly(ethylene glycol). J Pharmacol Exp Ther 280(3):1319–1327

    PubMed  CAS  Google Scholar 

  20. Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M, MabThera International Trial Group (2006) CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379–391

    Article  PubMed  CAS  Google Scholar 

  21. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M, German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) (2008) Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9(2):105–116

    Article  PubMed  CAS  Google Scholar 

  22. Rose PG (2005) Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarian cancer. Oncologist 10(3):205–214

    Article  PubMed  CAS  Google Scholar 

  23. Rueda A, Sabin P, Rifá J, Llanos M, Gómez-Codina J, Lobo F, García R, Herrero J, Provencio M, Jara C (2008) Grupo Oncológico para el Tratamiento y Estudio de los Linfomas (GOTEL) R-CHOP-14 in patients with diffuse large B-cell lymphoma younger than 70 years: a multicentre, prospective study. Hematol Oncol 26(1):27–32

    Article  PubMed  CAS  Google Scholar 

  24. Safra T (2003) Cardiac safety of liposomal anthracyclines. Oncologist 8(Suppl 2):17–24

    Article  PubMed  CAS  Google Scholar 

  25. Simůnek T, Stérba M, Popelová O, Adamcová M, Hrdina R, Gersl V, 1 (2009) Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep 61:154–171

    PubMed  Google Scholar 

  26. Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, Jones SE, Wadler S, Desai A, Vogel C, Speyer J, Mittelman A, Reddy S, Pendergrass K, Velez-Garcia E, Ewer MS, Bianchine JR, Gams RA (1997) Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15(4):1318–1332

    PubMed  CAS  Google Scholar 

  27. Symon Z, Peyser A, Tzemach D, Lyass E, Sucher E, Shezen E, Gabizon A (1999) Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes. Cancer 86(1):72–78

    Article  PubMed  CAS  Google Scholar 

  28. Takemura G, Fujiwara H, 5 (2007) Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis 49:330–352

    Article  PubMed  CAS  Google Scholar 

  29. Tsavaris N, Kosmas C, Vadiaka M, Giannouli S, Siakantaris MP, Vassilakopoulos T, Pangalis GA, 3 (2002) Pegylated liposomal doxorubicin in the CHOP regimen for older patients with aggressive (stages III/IV) non-Hodgkin's lymphoma. Anticancer Res 22:1845–1848

    PubMed  CAS  Google Scholar 

  30. van Dalen EC, Michiels EM, Caron HN, Kremer LC (2010) Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev 5:CD005006

    PubMed  Google Scholar 

  31. 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):710–717

    Google Scholar 

  32. Waterhouse DN, Tardi PG, Mayer LD, Bally MB (2001) A comparison of liposomal formulations of doxorubicin with drug administered in free form. Drug Saf 24(12):903–920

    Article  PubMed  CAS  Google Scholar 

  33. Yeh ET, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, Durand JB, Gibbs H, Zafarmand AA, Ewer MS (2004) Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 109(25):3122–3131

    Article  PubMed  Google Scholar 

  34. Zaja F, Tomadini V, Zaccaria A, Lenoci M, Battista M, Molinari AL, Fabbri A, Battista R, Cabras MG, Gallamini A, Fanin R (2006) CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma 47(10):2174–2180

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, University Hospital of Heidelberg, INF 410, 69120, Heidelberg, Germany

    Christian Johannes Schmitt, Sascha Dietrich, Antony Dick Ho & Mathias Witzens-Harig

Authors
  1. Christian Johannes Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sascha Dietrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antony Dick Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mathias Witzens-Harig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian Johannes Schmitt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmitt, C.J., Dietrich, S., Ho, A.D. et al. Replacement of conventional doxorubicin by pegylated liposomal doxorubicin is a safe and effective alternative in the treatment of non-Hodgkin's lymphoma patients with cardiac risk factors. Ann Hematol 91, 391–397 (2012). https://doi.org/10.1007/s00277-011-1308-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-011-1308-y

Keywords

Search

Navigation