Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines: a meta-analysis

Shamudheen M Rafiyath, Mohammad Rasul, Byung Lee, Guoqing Wei, Gurpreet Lamba, Delong Liu, Shamudheen M Rafiyath, Mohammad Rasul, Byung Lee, Guoqing Wei, Gurpreet Lamba, Delong Liu

Abstract

Background: Liposomal formulations of anthracyclines appear to have favorable toxicity profile when compared with conventional anthracyclines in elderly, high risk cardiac patients and patients with prior use of anthracyclines. Randomized controlled trials have evaluated the efficacy and safety profile of liposomal formulations with conventional anthracyclines. Our aim is to evaluate the adverse effects and quantify the relative safety profile of the liposomal and conventional anthracyclines through meta-analysis of the published randomized trials.

Methods: We conducted a broad search strategy of major electronic databases. We performed a meta- analysis of adverse effects on randomized controlled trials comparing liposomal formulation and conventional anthracyclines on different tumors. The primary outcome was the adverse effects including congestive heart failure (CHF), hematological toxicity, palmar-plantar erythrodysthesias (PPE), alopecia, nausea and vomiting. The odds ratios of the adverse effects were calculated separately and the overall odds ratio of the pooled data was calculated.

Results: We identified nine randomized controlled trials comparing liposomal formulations and conventional anthracyclines. The study included 2220 patients, of which1112 patients were treated with liposomal formulations and 1108 were treated with conventional anthracyclines. We found that the liposomal formulations have low incidence of CHF(OR 0.34, 95% CI, 0.24-0.47), alopecia (OR 0.0.25, 95% CI, 0.0.10-0.62), neutropenia (OR 0.62, 95% CI, 0.45- 0.85),(OR 0.89, 95% CI, 0.71-1.125), and thrombocytopenia (OR 0.87, 95% CI, 0.61-1.25). The incidence of PPE was similar in both arms (OR 1.08, 95% CI, 0.11- 10.30).

Conclusions: Liposomal doxorubicin and pegylated liposomal doxorubicin demonstrated favorable toxicity profiles with better cardiac safety and less myelosuppression, alopecia, nausea and vomiting compared with the conventional anthracyclines. The better therapeutic index of liposomal anthracyclines without compromising the efficacy makes it a favorable choice over conventional anthracyclines in elderly patients, patients with risk factors for cardiac disease and patients with prior use of anthracyclines.

Figures

Figure 1
Figure 1
Comparison of odds ratio in CHF. The summary of OR wwas calculated using the fixed effect model. Squares are ORs of CHF for separate trials Horizontal lines through the scores represent 95% CIs. The diamond represents the overall OR of CHF from the meta-analysis and the corresponding 95% CIs. The studies that enrolled liposomal doxorubicin and conventional anthracyclines were separated into two groups for this analysis. Abbreviations: CI: Confidence interval; OR: Odd ratio; CHF: Congestive Heart Failure.
Figure 2
Figure 2
Comparison of odds ratio in palmar-plantar erythrodysesthesia (PPE)/Hand foot syndrome (HFS). The summary of OR was calculated using the random effect model. Squares are ORs of PPE/HFS for separate trials. Horizontal lines through the squares represent 95% CIs. The diamond represents the overall OR of PPE/HFS from the meta-analysis and the corresponding 95% CIs. The horizontal line with an arrow indicates the trial with highest OR. The studies that enrolled liposomal doxorubicin and conventional anthracyclines were separated into two groups for this analysis. Abbreviations: CI: Confidence interval; OR: Odd ratio; PPE.
Figure 3
Figure 3
Comparison of odds ratio in alopecia. The summary of OR was calculated using the random effect model. Squares are ORs of alopecia for separate trials. Horizontal lines through the squares represent 95% CIs. The diamond represents the overall OR of alopecia from the meta-analysis and the corresponding 95% CIs. The horizontal line with an arrow indicates the trial with highest OR. The studies that enrolled liposomal doxorubicin and conventional anthracyclines were separated into two groups for this analysis. Abbreviations: CI: Confidence interval; OR: Odd ratio.
Figure 4
Figure 4
Comparison of odds ratio in neutropenia. The summary of OR was calculated using the random effect model. Squares are ORs of neutropenia for separate trials. Horizontal lines through the squares represent 95% CIs. The diamond represents the overall OR of neutropenia from the meta-analysis and the corresponding 95% CIs. The studies that enrolled liposomal doxorubicin and conventional anthracyclines were separated into two groups for this analysis. Abbreviations: CI: Confidence interval; OR: Odd ratio.
Figure 5
Figure 5
Comparison of odds ratio in febrile neutropenia. The summary of OR was calculated using the random effect model. Squares are ORs of febrile neutropenia for separate trials. Horizontal lines through the squares represent 95% CIs. The diamond represents the overall OR of Febrile Neutropenia from the meta-analysis and the corresponding 95% CIs. The horizontal line with an arrow indicates the trial with highest OR. The studies that enrolled liposomal doxorubicin and conventional anthracyclines were separated into two groups for this analysis. Abbreviations: CI: Confidence interval; OR: Odd ratio.

References

    1. Takahashi S. Current findings for recurring mutations in acute myeloid leukemia. J Hematol Oncol. 2011;4:36. doi: 10.1186/1756-8722-4-36.
    1. Takahashi S. Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications. J Hematol Oncol. 2011;4:13. doi: 10.1186/1756-8722-4-13.
    1. Zhu X, Ma Y, Liu D. Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights. J Hematol Oncol. 2010;3:17. doi: 10.1186/1756-8722-3-17.
    1. Rivera E. Liposomal anthracyclines in metastatic breast cancer: clinical update. Oncologist. 2003;8(Suppl 2):3–9.
    1. Barrett-Lee PJ, Dixon JM, Farrell C, Jones A, Leonard R, Murray N, Palmieri C, Plummer CJ, Stanley A, Verrill MW. Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2009;20(5):816–827. doi: 10.1093/annonc/mdn728.
    1. Zhang SH, Wang WQ, Wang JL. Protective effect of tetrahydroxystilbene glucoside on cardiotoxicity induced by doxorubicin in vitro and in vivo. Acta Pharmacol Sin. 2009;30(11):1479–1487. doi: 10.1038/aps.2009.144.
    1. O’Shaughnessy J. Liposomal anthracyclines for breast cancer: overview. Oncologist. 2003;8(Suppl 2):1–2.
    1. Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E, Group TDS. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer. 2002;94(1):25–36. doi: 10.1002/cncr.10201.
    1. Lopez-Berestein G, IJ Fidler, CIBA-GEIGY Corporation. Liposomes in the therapy of infectious diseases and cancer: proceedings of a Ciba-Geigy-Squibb-UCLA colloquium, held at Lake Tahoe, California, February 16–20, 1988. New York: Liss E.R. Squibb & Sons., University of California Los Angeles; 1989.
    1. Al-Batran SE, Meerpohl HG, von Minckwitz G, Atmaca A, Kleeberg U, Harbeck N, Lerbs W, Hecker D, Sehouli J, Knuth A. et al.Reduced incidence of severe palmar-plantar erythrodysesthesia and mucositis in a prospective multicenter phase II trial with pegylated liposomal doxorubicin at 40 mg/m2 every 4 weeks in previously treated patients with metastatic breast cancer. Oncology. 2006;70(2):141–146. doi: 10.1159/000093005.
    1. Safra T. Cardiac safety of liposomal anthracyclines. Oncologist. 2003;8(Suppl 2):17–24.
    1. Simunek T, Sterba M, Popelova O, Adamcova M, Hrdina R, Gersl V. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacological reports: PR. 2009;61(1):154–171.
    1. Allen TM, Mumbengegwi DR, Charrois GJ. Anti-CD19-targeted liposomal doxorubicin improves the therapeutic efficacy in murine B-cell lymphoma and ameliorates the toxicity of liposomes with varying drug release rates. Clinical cancer research: an official journal of the American Association for Cancer Research. 2005;11(9):3567–3573. doi: 10.1158/1078-0432.CCR-04-2517.
    1. O’Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP. et al.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. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2004;15(3):440–449. doi: 10.1093/annonc/mdh097.
    1. Balazsovits JA, Mayer LD, Bally MB, Cullis PR, McDonell M, Ginsberg RS, Falk RE. Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor efficacy of doxorubicin. Cancer Chemother Pharmacol. 1989;23(2):81–86.
    1. Batist G, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P, Khojasteh A, Nair MK, Hoelzer K. et al.Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2001;19(5):1444–1454.
    1. Kanter PM, Bullard GA, Ginsberg RA, Pilkiewicz FG, Mayer LD, Cullis PR, Pavelic ZP. Comparison of the cardiotoxic effects of liposomal doxorubicin (TLC D-99) versus free doxorubicin in beagle dogs. In Vivo. 1993;7(1):17–26.
    1. Kanter PM, Bullard GA, Pilkiewicz FG, Mayer LD, Cullis PR, Pavelic ZP. Preclinical toxicology study of liposome encapsulated doxorubicin (TLC D-99): comparison with doxorubicin and empty liposomes in mice and dogs. In Vivo. 1993;7(1):85–95.
    1. Mayer LD, Bally MB, Cullis PR, Wilson SL, Emerman JT. Comparison of free and liposome encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SC115 murine mammary tumor. Cancer Lett. 1990;53(2–3):183–190.
    1. Mayer LD, Tai LC, Bally MB, Mitilenes GN, Ginsberg RS, Cullis PR. Characterization of liposomal systems containing doxorubicin entrapped in response to pH gradients. Biochim Biophys Acta. 1990;1025(2):143–151. doi: 10.1016/0005-2736(90)90091-2.
    1. Franklin HR, Simonetti GP, Dubbelman AC, ten Bokkel Huinink WW, Taal BG, Wigbout G, Mandjes IA, Dalesio OB, Aaronson NK. Toxicity grading systems. A comparison between the WHO scoring system and the Common Toxicity Criteria when used for nausea and vomiting. Annals of oncology : official journal of the European Society for Medical Oncology/ESMO. 1994;5(2):113–117.
    1. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M, Kempin S, Silverberg I, Gonzales G. et al.Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi’s sarcoma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 1996;14(8):2353–2364.
    1. Northfelt DW, Dezube BJ, Thommes JA, Miller BJ, Fischl MA, Friedman-Kien A, Kaplan LD, Du Mond C, Mamelok RD, Henry DH. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi’s sarcoma: results of a randomized phase III clinical trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 1998;16(7):2445–2451.
    1. Judson I, Radford JA, Harris M, Blay JY, van Hoesel Q, le Cesne A, van Oosterom AT, Clemons MJ, Kamby C, Hermans C. et al.Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37(7):870–877. doi: 10.1016/S0959-8049(01)00050-8.
    1. Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A. et al.Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2003;14(7):1039–1044. doi: 10.1093/annonc/mdg287.
    1. Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, Lee LW. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2004;15(10):1527–1534. doi: 10.1093/annonc/mdh393.
    1. Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial. Cancer. 2006;106(4):848–858. doi: 10.1002/cncr.21662.
    1. Von Hoff DD, Layard MW, Basa P, Davis HL, Von Hoff AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91(5):710–717.
    1. Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11(2):193–206.
    1. Hu J, Zhao G, Wang HX, Tang L, Xu YC, Ma Y, Zhang FC. A meta-analysis of gemcitabine containing chemotherapy for locally advanced and metastatic pancreatic adenocarcinoma. J Hematol Oncol. 2011;4:11. doi: 10.1186/1756-8722-4-11.
    1. Wei G, Ni W, Chiao JW, Cai Z, Huang H, Liu D. A meta-analysis of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome. J Hematol Oncol. 2011;4:46. doi: 10.1186/1756-8722-4-46.

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