The use of pegylated liposomal doxorubicin in metastatic soft tissue sarcoma
DOI:
https://doi.org/10.2340/1651-226X.2025.43263Keywords:
sarcoma, treatment, survival, rare cancerAbstract
Background: Soft tissue sarcoma (STS) is a heterogeneous group of rare malignancies with limited response to conventional chemotherapy. Among these, epithelioid haemangioendothelioma (EHE) and angiosarcoma represent rare vascular sarcomas with distinct clinical behaviours, challenging treatment approaches, and poor prognoses. Doxorubicin remains the standard first-line therapy for metastatic STS, but its use is constrained by dose-dependent cardiotoxicity. Pegylated liposomal doxorubicin (PLD) has been proposed as an alternative.
Material and method: This retrospective, registry-based cohort study investigates the efficacy of PLD in patients with locally advanced or metastatic STS treated at Aarhus University Hospital, Denmark, between 2008 and 2023. Patients were identified from a regional database, and progression-free survival (PFS) and overall survival (OS) were analysed.
Results: A total of 38 patients were included, with 6 diagnosed with EHE and 16 with angiosarcoma. Among EHE patients, all had metastatic disease at diagnosis, with a median PFS of 7.8 months and OS of 1.5 years from the start of PLD treatment. Two patients remained progression-free for over 5 years. In angiosarcoma patients, the median PFS was 7.4 months, and the median OS was 2.4 years. Other STS subtype including solitary fibrous tumours (SFT), showed minimal benefit from PLD, with a median PFS of 2.8 months.
Interpretation: Pegylated liposomal doxorubicin demonstrated clinically relevant activity in angiosarcoma and EHE. It may be considered a therapeutic option for patients with these aggressive vascular sarcomas. Further prospective studies are warranted to confirm its efficacy and optimised treatment strategies.
Downloads
References
Meyer M, Seetharam M. First-line therapy for metastatic soft tissue sarcoma. Curr Treat Options Oncol. 2019;20(1):6.
https://doi.org/10.1007/s11864-019-0606-9 DOI: https://doi.org/10.1007/s11864-019-0606-9
Bauer S, Hartmann JT. Locally advanced and metastatic sarcoma (adult type) including gastrointestinal stromal tumors. Crit Rev Oncol Hematol. 2006;60(2):112–30.
https://doi.org/10.1016/j.critrevonc.2006.06.010 DOI: https://doi.org/10.1016/j.critrevonc.2006.06.010
Skubitz KM, Haddad PA. Paclitaxel and pegylated-liposomal doxorubicin are both active in angiosarcoma. Cancer. 2005;104(2):361–6.
https://doi.org/10.1002/cncr.21140 DOI: https://doi.org/10.1002/cncr.21140
Ravi V, Patel S. Vascular sarcomas. Curr Oncol Rep. 2013;15(4):347–55.
https://doi.org/10.1007/s11912-013-0328-2 DOI: https://doi.org/10.1007/s11912-013-0328-2
Cioffi A, Reichert S, Antonescu CR, Maki RG. Angiosarcomas and other sarcomas of endothelial origin. Hematol Oncol Clin North Am. 2013;27(5):975–88.
https://doi.org/10.1016/j.hoc.2013.07.005 DOI: https://doi.org/10.1016/j.hoc.2013.07.005
Lau K, Massad M, Pollak C, Rubin C, Yeh J, Wang J, et al. Clinical patterns and outcome in epithelioid hemangioendothelioma with or without pulmonary involvement: insights from an internet registry in the study of a rare cancer. Chest. 2011;140(5):1312–8.
https://doi.org/10.1378/chest.11-0039 DOI: https://doi.org/10.1378/chest.11-0039
De Pinieux G, Karanian M, Le Loarer F, Le Guellec S, Chabaud S, Terrier P, et al. Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network. PLoS One. 2021;16(2):e0246958.
https://doi.org/10.1371/journal.pone.0246958 DOI: https://doi.org/10.1371/journal.pone.0246958
Rosenberg A, Agulnik M. Epithelioid hemangioendothelioma: update on diagnosis and treatment. Curr Treat Options Oncol. 2018;19(4):19.
https://doi.org/10.1007/s11864-018-0536-y DOI: https://doi.org/10.1007/s11864-018-0536-y
Grenader T, Vernea F, Reinus C, Gabizon A. Malignant epithelioid hemangioendothelioma of the liver successfully treated with pegylated liposomal doxorubicin. J Clin Oncol. 2011;29(25):e722–4.
https://doi.org/10.1200/JCO.2011.35.5891 DOI: https://doi.org/10.1200/JCO.2011.35.5891
Stacchiotti S, Frezza AM, Blay JY, Baldini EH, Bonvalot S, Bovée J, et al. Ultra-rare sarcomas: a consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities. Cancer. 2021;127(16):2934–42.
https://doi.org/10.1002/cncr.33618 DOI: https://doi.org/10.1002/cncr.33618
Toma S, Tucci A, Villani G, Carteni G, Spadini N, Palumbo R. Liposomal doxorubicin (Caelyx) in advanced pretreated soft tissue sarcomas: a phase II study of the Italian Sarcoma Group (ISG). Anticancer Res. 2000;20(1b):485–91.
(DMCG) DMCg. Kliniske retningslinjer. Pallierende kemoterapi og targeteret behandling til patienter med bløddelssarkom. 2022. Sammenslutningen af 25 danske Multidisciplinære Cancer grupper og Sekretariatet for Kliniske Retningslinjer på kræftområdet, Aarhus N.
O’Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, 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. Ann Oncol. 2004;15(3):440–449.
https://doi.org/10.1093/annonc/mdh097 DOI: https://doi.org/10.1093/annonc/mdh097
Soloman R, Gabizon AA. Clinical pharmacology of liposomal anthracyclines: focus on pegylated liposomal Doxorubicin. Clin Lymphoma Myeloma. 2008;8(1):21–32.
https://doi.org/10.3816/CLM.2008.n.001 DOI: https://doi.org/10.3816/CLM.2008.n.001
Judson I, Radford JA, Harris M, Blay JY, Van Hoesel Q, Le Cesne A, 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):870–7.
https://doi.org/10.1016/S0959-8049(01)00050-8
Grenader T, Goldberg A, Hadas-Halperin I, Gabizon A. Long-term response to pegylated liposomal doxorubicin in patients with metastatic soft tissue sarcomas. Anticancer Drugs. 2009;20(1):15–20.
https://doi.org/10.1097/CAD.0b013e3283198058 DOI: https://doi.org/10.1097/CAD.0b013e3283198058
Savani M, Murugan P, Skubitz KM. Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure. Clin Sarcoma Res. 2019;9:1.
https://doi.org/10.1186/s13569-018-0111-0 DOI: https://doi.org/10.1186/s13569-018-0111-0
Stacchiotti S, Miah AB, Frezza AM, Messiou C, Morosi C, Caraceni A, et al. Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts. ESMO Open. 2021;6(3):100170.
https://doi.org/10.1016/j.esmoop.2021.100170 DOI: https://doi.org/10.1016/j.esmoop.2021.100170
Engel ER, Cournoyer E, Adams DM, Stapleton S. A retrospective review of the use of sirolimus for pediatric patients with epithelioid hemangioendothelioma. J Pediatr Hematol Oncol. 2020;42(8):
e826–e9.
https://doi.org/10.1097/MPH.0000000000001643 DOI: https://doi.org/10.1097/MPH.0000000000001643
Stacchiotti S, Simeone N, Lo Vullo S, Baldi GG, Brunello A, Vincenzi B, et al. Activity of sirolimus in patients with progressive epithelioid hemangioendothelioma: a case-series analysis within the Italian Rare Cancer Network. Cancer. 2021;127(4):569–76.
https://doi.org/10.1002/cncr.33247 DOI: https://doi.org/10.1002/cncr.33247
Kollar A, Jones RL, Stacchiotti S, Gelderblom H, Guida M, Grignani G, et al. Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) retrospective analysis. Acta Oncol (Stockholm, Sweden). 2017;56(1):88–92.
https://doi.org/10.1080/0284186X.2016.1234068 DOI: https://doi.org/10.1080/0284186X.2016.1234068
Penel N, Bui BN, Bay JO, Cupissol D, Ray-Coquard I, Piperno-Neumann S, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008;26(32):5269–74.
https://doi.org/10.1200/JCO.2008.17.3146 DOI: https://doi.org/10.1200/JCO.2008.17.3146
Ray-Coquard IL, Domont J, Tresch-Bruneel E, Bompas E, Cassier PA, Mir O, et al. Paclitaxel given once per week with or without bevacizumab in patients with advanced angiosarcoma: a randomized Phase II trial. J Clin Oncol. 2015;33(25):2797–802.
https://doi.org/10.1200/JCO.2015.60.8505 DOI: https://doi.org/10.1200/JCO.2015.60.8505
Italiano A, Cioffi A, Penel N, Levra MG, Delcambre C, Kalbacher E, et al. Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas. Cancer. 2012;118(13):3330–6.
https://doi.org/10.1002/cncr.26599 DOI: https://doi.org/10.1002/cncr.26599
Judson I, Radford JA, Harris M, Blay JY, Van Hoesel Q, Le Cesne A, 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 (Oxford, England: 1990). 2001;37(7):870–7.
https://doi.org/10.1016/S0959-8049(01)00050-8 DOI: https://doi.org/10.1016/S0959-8049(01)00050-8
Fury MG, Antonescu CR, Van Zee KJ, Brennan MF, Maki RG. A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J (Sudbury, Mass). 2005;11(3):241–7.
https://doi.org/10.1097/00130404-200505000-00011 DOI: https://doi.org/10.1097/00130404-200505000-00011
Wei H, Mao J, Wu Y, Zhou Q. Case report: postoperative recurrence of adrenal epithelioid angiosarcoma achieved complete response by combination chemotherapy with liposomal doxorubicin and paclitaxel. Front Oncol. 2021;11:791121.
https://doi.org/10.3389/fonc.2021.791121 DOI: https://doi.org/10.3389/fonc.2021.791121
Tian Z, Yang Y, Yang J, Zhang P, Zhang F, Du X, et al. Safety and efficacy of PD-1 inhibitors plus chemotherapy in advanced soft tissue sarcomas: a retrospective study. Cancer Manag Res. 2020;12:
1339–46.
https://doi.org/10.2147/CMAR.S237300 DOI: https://doi.org/10.2147/CMAR.S237300
Italiano A, Bellera C, D’Angelo S. PD1/PD-L1 targeting in advanced soft-tissue sarcomas: a pooled analysis of phase II trials. J Hematol Oncol. 2020;13(1):55.
https://doi.org/10.1186/s13045-020-00891-5 DOI: https://doi.org/10.1186/s13045-020-00891-5
Published
How to Cite
Issue
Section
Categories
License
Copyright (c) 2025 Trang Pham, Hanne Krogh Rose, Philip Rossen, Ninna Aggerholm Pedersen
This work is licensed under a Creative Commons Attribution 4.0 International License.
