liposomal doxorubicin vs doxorubicin

Cancer Lett 1990,53(23):183190. Five trials used pegylated liposomal doxorubicin. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO 2003,14(7):10391044. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M, Kempin S, Silverberg I, Gonzales G, et al. Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines: a meta-analysis. The studies that enrolled liposomal doxorubicin and conventional anthracyclines were separated into two groups for this analysis. We also searched unpublished studies with results through clinical trials.gov and the American Society of Clinical Oncology (ASCO) website. doxorubicin liposomal stru hydrochloride injection ndc California Privacy Statement, Annals of oncology: official journal of the European Society for Medical Oncology/ESMO 2004,15(3):440449. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. The toxicity increases with high peak plasma anthracycline levels [9]. Abbreviations: CI: Confidence interval; OR: Odd ratio. Would you like email updates of new search results? Google Scholar. 1998 Jul;16(7):2445-51 Epub 2021 Mar 31. liposomal doxorubicin ultrasound repeated multiforme glioblastoma treating induced selective dose chemotherapy focused were ap liposome representation schematic liposomes conjugated prepared : 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. Unlike Doxil, the myocet liposome does not have a polyethylene glycol coating and therefore does not result in the same prevalence of Hand-Foot Syndrome. This article is published under license to BioMed Central Ltd. The need for further testing of the liposomal formulations prior to the replacement of free doxorubicin with liposomal doxorubicin in any established combination therapy regimens, as well as in combination with the newer therapeutics such as monoclonal antibodies is also discussed. 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. First we identified key terms of the study drugs liposomal doxorubicin, Doxil Myocet, Doxorubicin, Daunorubicin, Epirubicin,Mitoxantrone,and Idarubicin. In Vivo 1993,7(1):8595. Pharmacokinetics, efficacy and toxicity of different pegylated liposomal doxorubicin formulations in preclinical models: is a conventional bioequivalence approach sufficient to ensure therapeutic equivalence of pegylated liposomal doxorubicin products? Exp Hematol Oncol 1, 10 (2012). Northfelt, OBrien and Batist plotted the relationship of cumulative dose of liposomal anthracyclines and conventional anthracyclines [14, 16, 23]. Takahashi S: Current findings for recurring mutations in acute myeloid leukemia.

Batist G, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P, Khojasteh A, Nair MK, Hoelzer K, et al.

The risk of cardiotoxicity increases with higher cumulative doses of anthracyclines [47]. The heterogeneity of the studies was low and the I showed moderate heterogeneity for the cardiac toxicity. Horizontal lines through the squares represent 95% CIs. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 1996,14(8):23532364. Though there was no difference within the study in each group, there were variations among different studies based on various factors. Otherwise, fixed- effect model was used for the data analysis. J Hematol Oncol 2011, 4: 11. Bethesda, MD 20894, Web Policies Open Access

Oncologist 2003,8(Suppl 2):12. Minimizing cardiac toxicity in children with acute myeloid leukemia. 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 Chan, Dimpoulos, Gill, Harris and Northfelt studies were in favor of the non liposomal anthracyclines. Leonard RC, Williams S, Tulpule A, Levine AM, Oliveros S. Breast. 1112 patients were treated with liposome encapsulated anthracyclines, including 666 who received PLD, 330 who received LD, and 116 who received liposomal daunorubicin. The median cumulative dose of the doxorubicin in both forms was reported in six of the eight trials analyzed. Eur J Cancer 2001,37(7):870877. Hematology Am Soc Hematol Educ Program. Google Scholar. Springer Nature. 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. Squares are ORs of neutropenia for separate trials. Article Boix-Montesinos P, Soriano-Teruel PM, Armin A, Orzez M, Vicent MJ. However, as will be discussed, the liposomal formulations of doxorubicin are not without their own related toxicities, and, in the case of Doxil, may be associated with the unique toxicity of palmar-plantar erythrodysaesthesia. 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. Below are the links to the authors original submitted files for images. The odds ratios of all 9 studies were analyzed. In the study by Chan et al., the number of patients with decrease in LVEF under a cumulative dose of <450mg/m2 were 5 and 8 for liposomal doxorubicin and epirubicin, respectively. Google Scholar, Zhang SH, Wang WQ, Wang JL: Protective effect of tetrahydroxystilbene glucoside on cardiotoxicity induced by doxorubicin in vitro and in vivo. Annals of oncology : official journal of the European Society for Medical Oncology/ESMO 1994,5(2):113117. 10.1159/000093005. The randomized controlled trials on pegylated liposomal doxorubicin (Doxil/CAELYX), non-pegylated liposomal doxorubicin (Myocet), and liposomal Daunorubicin (DaunoXome) pooled for the meta-analysis, irrespective of tumor types and stages. Horizontal lines through the squares represent 95% CIs. -, J Urol. PubMed The site is secure. PubMed Central 10.1002/cncr.21662. Oncologist 2003,8(Suppl 2):39. 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 Kaposis sarcoma: results of a randomized phase III clinical trial. This meta-analysis included nine randomized controlled trials comparing liposomal and conventional anthracyclines. 2010 Dec;54(4):359-67. doi: 10.1556/MOnkol.54.2010.4.10. We identified nine randomized controlled trials comparing liposomal formulations and conventional anthracyclines. One study showed similar toxicity on both arms.

Magy Onkol. The .gov means its official. 2021 Jan 13;13(1):93. doi: 10.3390/pharmaceutics13010093. Google Scholar. Article Following administration of Doxil, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. Therefore, the overall result of the nine trials did not show statistically significant advantage of conventional anthracyclines over liposomal preparations in PPE events. 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. The information about the cumulative dose and cardiac toxicity was extrapolated in a separate excel sheet. The incidence of hematological toxicity of all grades was lower with liposomal anthracyclines. Abbreviations: CI: Confidence interval; OR: Odd ratio; CHF: Congestive Heart Failure. The diamond represents the overall OR of Febrile Neutropenia from the meta-analysis and the corresponding 95% CIs. Ferrero A, Borghese M, Restaino S, Puppo A, Vizzielli G, Biglia N. Int J Environ Res Public Health. The summary of OR was calculated using the random effect model. 1994;2(5):397-403 The information of the different grades of hematology toxicity was not available in two of the trials. J Hematol Oncol 2011, 4: 46. J Hematol Oncol 2010, 3: 17. 10.1158/1078-0432.CCR-04-2517, OBrien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, et al. 10.1186/1756-8722-4-46. 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. HHS Vulnerability Disclosure, Help We used a variety of electronic databases, including MEDLINE via Pub MED, Ovid, and the Cochrane library. [Non-pegylated doxorubicin (Myocet) as the less cardiotoxic alternative of free doxorubicin]. and transmitted securely. The cardiac safety profile of the liposomal formulations of anthracyclines suggests the potential to use it in combination with trastuzumab in HER2 positive breast cancer. Due to the different tumor types, the study drugs varied in the dose, frequency and number of treatment. Squares are ORs of alopecia for separate trials. Two studies did not include the information about nausea and vomiting. The horizontal line with an arrow indicates the trial with highest OR. All these trials compared PLD with doxorubicin. Pharmacological reports: PR 2009,61(1):154171. However, the intergroup variations have a limited effect on our meta-analysis due to the fact that each trial is randomized and well controlled.

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. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO 2004,15(10):15271534. Cite this article. The overall ORs were calculated from the pooled data. Psychol Methods 2006,11(2):193206. The variables for the adverse effects include cardiac toxicity, hematology toxicity, hand-foot syndrome or palmar plantar erythrodysesthesia (PPE), febrile neutropenia, alopecia, nausea and vomiting. Thus, liposomes should preferentially direct doxorubicin away from sites of potential toxicity, but leave the tumor exposed [11]. Provided by the Springer Nature SharedIt content-sharing initiative. The majority of the trials (6 out of 9) used the National Cancer Institute-Common Toxicity Criteria (NCI-CTC). 2022 BioMed Central Ltd unless otherwise stated. 2022 Apr 2;19(7):4260. doi: 10.3390/ijerph19074260. 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. Abbreviations: CI: Confidence interval; OR: Odd ratio. The pooled analyses were statistically significantly in favor of the liposomal arm compared with the conventional anthracyclines. Acta Pharmacol Sin 2009,30(11):14791487. In the study by Batist et al., the estimated median cumulative life time dose for cardiac toxicity was 2220mg/m2 for the liposomal group and 480mg/m2 for the non liposomal group. The combined odds ratio for the pooled result is 0.335 (95% CI (0.2380.471, p=0.086). The odds ratios of Batist, Judson, Northfelt and Rifkin studies were in favor of the liposomal arm.

Incomplete ongoing randomized trials with no published results were excluded as well. 10.1186/1756-8722-4-11, 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. Bookshelf Cancer Chemother Pharmacol 1989,23(2):8186. Google Scholar, 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. The remaining two trials used the WHO criteria for toxicity and one trial used South West Oncology Group (SWOG) toxicity scoring system. The horizontal line with an arrow indicates the trial with highest OR. The past, present, and future of breast cancer models for nanomedicine development. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License (

Repeated damage to the mitochondria of myocytes by the free radicals is believed to contribute to cumulative cardiomyopathy [10]. OShaughnessy J: Liposomal anthracyclines for breast cancer: overview. Doxil has preferential concentration in the skin because of the polyethylene glycol coating. The study included 2220 patients, of which1112 patients were treated with liposomal formulations and 1108 were treated with conventional anthracyclines. J Drug Target. Abbreviations: CI: Confidence interval; OR: Odd ratio; PPE. -, Cancer Chemother Pharmacol. Analysis of cardiotoxicity included comparison of the proportion of patients in each treatment group who developed cardiotoxicity (by protocol specified cardiac event) at any time during the study, as well as comparison of the mean percentage change in LVEF from baseline. Disclaimer, National Library of Medicine The minimization of this side effect may allow 1: 1 substitution with doxorubicin in the same treatment regimen, thereby improving safety with no loss of efficacy. CAS The summary of OR wwas calculated using the fixed effect model. The summary of OR was calculated using the random effect model. The primary end points were the adverse effects: cardiac toxicity with congestive cardiac failure and significant reduction in the left ventricular ejection fraction (LVEF) were entered in separate arms. The selected randomized articles were again searched for related topics on the Pub MED database. The https:// ensures that you are connecting to the Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines: a meta-analysis, https://creativecommons.org/licenses/by/2.0. The adverse effects of the liposomal and conventional anthracyclines were analyzed in two arms. Alopecia, either partial or complete, was analyzed as one variable. Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella J: Assessing heterogeneity in meta-analysis: Q statistic or I2 index? The diamond represents the overall OR of neutropenia from the meta-analysis and the corresponding 95% CIs. Squibb & Sons., University of California Los Angeles; 1989, Al-Batran SE, Meerpohl HG, von Minckwitz G, Atmaca A, Kleeberg U, Harbeck N, Lerbs W, Hecker D, Sehouli J, Knuth A, et al. One of the key toxicity issues linked to the use of free doxorubicin is that of both an acute and a chronic form of cardiomyopathy. Division of Hematology and Oncology, New York Medical College and Westchester Medical Center, Valhalla, NY, 10595, USA, Shamudheen M Rafiyath,Mohammad Rasul,Byung Lee,Gurpreet Lamba&Delong Liu, Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, You can also search for this author in The incidence of alopecia (Figure 3) showed consistent results in 5 studies, whereas three studies showed no significant difference in the incidence of alopecia. 10.1186/1756-8722-3-17, PubMed Central Overall, the use of liposomal doxorubicin allows for a greater lifetime cumulative dose of doxorubicin to be administered, however acute maximal tolerated doses differ significantly, with that of Myocet being essentially equivalent to free doxorubicin, while higher doses of Doxil may be safely administered. Experimental Hematology & Oncology Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet). Randomized controlled trials with two different anthracyclines, but neither of them are a liposomal anthracycline were also excluded. The trials [14, 2325, 27] showed significantly lower incidence of alopecia. PubMed MeSH To our knowledge this is the first meta-analysis comparing the safety of the conventional anthracyclines and the liposome encapsulated anthracyclines. All randomized controlled trials that compared the efficacy of the liposome encapsulated doxorubicin with the conventional anthracyclines on any cancer with or without other chemotherapy were considered eligible for the analysis. PPE is a dose limiting toxicity of pegylated liposomal doxorubicin, doxil, which is the only liposomal doxorubicin approved in USA, even though the meta-analysis did not show significant differences in PPE. 2009 Aug;18(4):218-24. doi: 10.1016/j.breast.2009.05.004. Terms and Conditions, 10.1186/1756-8722-4-36, CAS Comparison of odds ratio in febrile neutropenia. BL, GL and GW participated in reference preparation and formatting. 1993;33(2):107-12 Epub 2009 Aug 4. Squares are ORs of febrile neutropenia for separate trials. Article Doxil/Caelyx is a Pegylated (polyethylene glycol coated) liposome-encapsulated (PLD) form of doxorubicin [4, 7, 14]. : 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. The odds ratios for PPE in five trials were in favor of the liposomal arm, the other four trials favored of the non-liposomal anthracyclines. The three trials [8, 16, 26] that compared myocet with conventional anthracyclines failed to show a significant difference in the alopecia incidence. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2001,19(5):14441454. The incidence was counted for all grades of neutropenia. The liposomal formulation of doxorubicin. Cancer 2006,106(4):848858. The existence of heterogeneity among the study group was evaluated using the chi-squared analysis. It is recommended that the cumulative life time dose of doxorubicin should not exceed 450500mg/m2. The odd ratios of anemia and thrombocytopenia were 0.89(CI; 0.711.12) and 0.87(CI; 0.611.25) respectively. The odds ratio for the study conducted by Chan [26] and Dimopoulos [25] were 1.14 and 1.45, respectively, which is in favor of the non liposomal arm. The combined odds ratio of the trials were 1.08 (95% CI 0.11-10.30, p=0.947). The median cumulative dose is higher with the liposomal formulation in three of the trials [22, 23, 27], lower in one trial [14] and same in two trials [16, 24]. The cardiotoxicity (Figure 1) was higher with the doxorubicin group in five trails, whereas three other trials [14, 25, 26] did not show significant difference in cardiac toxicity in both doxorubicin and liposomal doxorubicin group. The prevalence of this side effect limits the Doxil dose that can be given as compared with doxorubicin in the same treatment regimen. Randomized controlled trials have evaluated the efficacy and safety profile of liposomal formulations with conventional anthracyclines. Abbreviations: CI: Confidence interval; OR: Odd ratio. Federal government websites often end in .gov or .mil. We conducted a broad search strategy of major electronic databases. Liposomal doxorubicin was associated with significantly less cardiac and gastrointestinal toxicity, while antitumor efficacy was at least comparable to that of the parent molecule [12, 13]. 8600 Rockville Pike Rivera E: Liposomal anthracyclines in metastatic breast cancer: clinical update. Anthracyclines have become one of the most important drugs for the treatment of both hematological and solid tumors [13]. This is circumvented by the use of liposomal formulations, as these systems tend to sequester the drug away from organs such as the heart, with greater accumulation in liver, spleen and tumours. -. Biochim Biophys Acta 1990,1025(2):143151. The diamond represents the overall OR of alopecia from the meta-analysis and the corresponding 95% CIs. The pooled result is in favor of the liposomal doxorubicin with an Odds ratio of 0.62 (95% CI is 0.450.85, p=0.003). The change in LV function and CHF above and below the cumulative dose of 450mg/m2 was lower with liposomal doxorubicin in OBrien [14] and Batist [16] studies. Myocet is a non-pegylated liposomal doxorubicin which is approved in Europe and Canada for treatment of metastatic breast cancer in combination with cyclophosphamide. Non randomized trials were excluded. Accessibility : Reduced incidence of severe palmar-plantar erythrodysesthesia and mucositis in a prospective multicenter phase II trial with pegylated liposomal doxorubicin at 40mg/m2 every 4weeks in previously treated patients with metastatic breast cancer. To minimize the bias, we used random effects models for the studies with high heterogeneity, as recommended and performed by many statisticians and meta-analysis publications [2931]. An official website of the United States government. : 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. volume1, Articlenumber:10 (2012) Oncology 2006,70(2):141146. Correspondence to PubMedGoogle Scholar. Nine randomized controlled trials that enrolled a total of 2220 patients were selected for the meta-analysis (Table 1). https://creativecommons.org/licenses/by/2.0 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. Horizontal lines through the squares represent 95% CIs. 10.1038/aps.2009.144. All authors read and approved the final manuscript. Privacy Squares are ORs of PPE/HFS for separate trials. Outside the United States, Doxil is known as Caelyx. Comparison of odds ratio in palmar-plantar erythrodysesthesia (PPE)/Hand foot syndrome (HFS). 2021 Jun;173:306-330. doi: 10.1016/j.addr.2021.03.018. J Hematol Oncol 2011, 4: 13. Anthracycline cardiotoxicity is an issue not only when it is administered as a single agent, but also when it is combined with other agents such as trastuzumab, which is a cardio toxic agent by itself [8]. -, J Clin Oncol. This site needs JavaScript to work properly. Article This review highlights the differences in both toxicity and pharmacokinetic properties between free doxorubicin and the different liposomal formulations, as have been determined in pre-clinical and clinical testing against a number of different human neoplasms. 1998 Feb;1(2):491-4 Comparison of odds ratio in CHF. Franklin HR, Simonetti GP, Dubbelman AC, ten Bokkel Huinink WW, Taal BG, Wigbout G, Mandjes IA, Dalesio OB, Aaronson NK: Toxicity grading systems. The horizontal line with an arrow indicates the trial with highest OR. In addition to the use of free, unencapsulated doxorubicin, there are two US Food and Drug Administration approved liposomal formulations of doxorubicin currently available, with several additional liposomal formulations being researched either in the laboratory or in clinical trials. Different criteria were used to define the grade of toxicity. SMR and DL participated in concept design, data collection and analysis, drafting and critically revising the manuscript. 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 antracyclines. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 1998,16(7):24452451. The rationale behind its design is similar to Doxil [1520]. Nanonutraceuticals: Anti-Cancer Activity and Improved Safety of Chemotherapy by Costunolide and Its Nanoformulation against Colon and Breast Cancer. The anthracycline antibiotic doxorubicin has wide activity against a number of human neoplasms and is used extensively both as a single agent and in combination regimens. 2021. The two approved liposomal formulations of doxorubicin have significantly different lipid compositions and loading techniques, which lead to both unique pharmacokinetic and toxicity profiles, distinct from those of the unencapsulated form. The controlled arms must include one of the conventional anthracyclines, epirubicin, daunorubicin, doxorubicin, idarubicin and mitoxantrone. The trials included four metastatic breast cancer trials, two multiple myeloma trials, two AIDS-related soft tissue sarcoma trials and one metastatic soft tissue sarcoma trials. Von Hoff DD, Layard MW, Basa P, Davis HL, Von Hoff AL, Rozencweig M, Muggia FM: Risk factors for doxorubicin-induced congestive heart failure. This article discusses the toxicities associated with the free form of doxorubicin, as well as those associated with the two most common liposomal formulations, namely Doxil and Myocet. Delong Liu. Randomized trials comparing liposomal anthracyclines with conventional anthracyclines invariably present similar or higher efficacy with the liposomal anthracyclines. 2021 Aug 10;9(8):990. doi: 10.3390/biomedicines9080990. A comparison between the WHO scoring system and the Common Toxicity Criteria when used for nausea and vomiting.