The role of Ifosfamide–doxorubicin chemotherapy in histology-specific, high grade, locally advanced soft tissue sarcoma, a 14-year experience

Published:November 07, 2021DOI:


      • Outcomes of high grade STS were comparedwith or without Ifosfamide–Doxorubicin.
      • Histology included Synovial Cell, DDL, Myxofibrosarcoma, RCLS, UPS, and US-NOS.
      • Suggests improved DMFS, DSS and OS using chemotherapy in selected patients.



      To compare long-term outcomes of high-grade, primary soft-tissue-sarcoma (STS), using Ifosfamide–Doxorubicin vs local therapy alone, in histology-specific sarcomas.


      Retrospective analysis was performed on 127 patients from 2005 to 2018, with high-grade STS of extremity or trunk, >5 cm, that were either Synovial-Cell, Dedifferentiated-Liposarcoma (DDL), Myxofibrosarcoma, Round-Cell-Liposarcoma (RCLS), Undifferentiated-Pleomorphic-Sarcoma (UPS), or Undifferentiated-Sarcoma-not-otherwise-specified (US-NOS), with central pathology review. Ifosfamide–Doxorubicin was generally given neoadjuvant over 5 cycles, followed by radiation and wide excision, with chemotherapy given in 38 patients, while 89 received local therapy alone. Multi-variable-analysis (MVA) of prognostic factors was performed, and local-recurrence-free-survival (LRFS), distant-metastases-free-survival (DMFS), disease-specific-survival (DSS), and overall-survival (OS) were estimated using Kaplan–Meier, and adjusted using propensity-score matching.


      Median follow-up was 4.5 years. Younger age (p < 0.0001) and Synovial histology (p = 0.0002) were more likely to undergo chemotherapy. Ifosfamide–Doxorubicin improved 5-year DMFS (p = 0.02), DSS (p = 0.01), and OS (p = 0.01), by univariate comparisons, as well as sub-analysis of non-synovial histology, but significance was lost after propensity-score matching for DMFS (p = 0.10), DSS (p = 0.09), and OS (p = 0.07). Size >10 cm, trunk location, and lack of chemotherapy significantly lowered DMFS, DSS, and OS on MVA, while DDL had more favorable survival; although size, trunk location, and DDL histology were not significantly different between treatment groups. Ifosfamide–Doxorubicin independently improved DMFS (p = 0.001), DSS (p = 0.01), and OS (p = 0.001) on MVA.


      Ifosfamide–Doxorubicin may be more beneficial in younger patients with >5 cm, high-grade, STS of the trunk or extremity in Synovial-Cell, DDL, Myxofibrosarcoma, RCLS, UPS, and US-NOS.


      DDL (Dedifferentiated-Liposarcoma), DMFS (distant-metastases-free-survival), DSS (disease-specific-survival), FNCLCC (Federation-Nationale-des-Centres-de-Lutte-Contra-le-Cancer), LRFS (local-recurrence-free-survival), MPNST (Malignant-Peripheral-Nerve-Sheath-Tumors), MVA (multivariable-analysis), OS (overall-survival), RCLS (Round-Cell-Liposarcoma), STS (soft-tissue-sarcoma), UPS (Undifferentiated-Pleomorphic-Sarcoma), US-NOS (Undifferentiated-Sarcoma-not-otherwise-specified)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Radiotherapy and Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Sarcoma Meta-Analysis Collaboration
        Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: meta-analysis of individual data.
        Lancet. 1997; 350: 1647-1654
        • Frustaci S.
        • Gherlinzoni F.
        • DePaoli A.
        • et al.
        Adjuvant chemotherapy for adult soft tissue sarcoma of the extremities and girdles: results of the Italian randomized cooperative trial.
        J Clin Oncol. 2001; 19: 1238-1247
        • Pervaiz N.
        • Colterjohn N.
        • Farrokhyar F.
        • Tozer R.
        • Figueredo A.
        • Ghert M.
        A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma.
        Cancer. 2008; 113: 573-581
        • Eilber F.C.
        • Rosen G.
        • Eckardt J.
        • Forscher C.
        • Nelson S.D.
        • Selch M.
        • et al.
        Treatment-induced pathologic necrosis: A predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas.
        J Clin Oncol. 2001; 19: 3203-3209
        • Edge S.B.
        • Byrd D.R.
        • Compton C.C.
        • et al.
        AJCC cancer staging handbook.
        7th ed. Springer, Chicago, IL2010
        • Kaplan E.L.
        • Meier P.
        Non-parametric estimation from incomplete observations.
        J Am Stat Assoc. 1958; 53: 457-481
        • Cox D.R.
        Regression models and life tables.
        JR Stat Soc B. 1972; 34: 187-202
        • Rosenbaum P.R.
        • Rubin D.B.
        Reducing bias in observation studies using subclassification on the propensity score.
        J Am Stat Assoc. 1984; 79: 516-524
      1. Eilber FC, Brennan MF, Eilber FR, et al. Chemotherapy is associated with improved survival in adult patients with primary extremity synovial sarcoma. Ann Surg 2007;246:105-113.

      2. Eilber FC, Eilber FR, Eckardt J, et al. The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma. Ann Surg 2004; 240:686-697.

        • Gronchi A.
        • Palmerini E.
        • Quagliuolo V.
        • Martin Broto J.
        • Lopez Pousa A.
        • Grignani G.
        • et al.
        Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: final results of a randomized trial from Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) sarcoma groups.
        J Clin Oncol. 2020; 38: 2178-2186
        • Sleijfer S.
        • Ouali M.
        • van Glabbeke M.
        • Krarup-Hansen A.
        • Rodenhuis S.
        • Le Cesne A.
        • et al.
        Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: An exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG).
        Eur J Cancer. 2010; 46: 72-83
        • Lorigan P.
        • Verweji J.
        • Papai Z.
        • et al.
        Phase III trial of two investigational schedules of Ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: A European Organization for Research and Treatment of cancer soft tissue and bone sarcoma group study.
        J Clin Oncol. 2007; 25: 3144-3150