Body composition as a predictor of toxicity after treatment with eribulin for advanced soft tissue sarcoma

  • Hiroshi KobayashiEmail author
  • Tomotake Okuma
  • Hiroyuki Oka
  • Koichi Okajima
  • Yuki Ishibashi
  • Liuzhe Zhang
  • Toshihide Hirai
  • Takahiro Ohki
  • Yusuke Tsuda
  • Masachika Ikegami
  • Ryoko Sawada
  • Yusuke Shinoda
  • Toru Akiyama
  • Hirotaka Kawano
  • Takahiro Goto
  • Sakae Tanaka
Original Article



Despite the clinical benefits of eribulin on overall survival of advanced soft tissue sarcoma (STS) patients, treatment-related toxicity reduces their QOL. Body composition metrics (BCMs) are associated with poor outcome and drug toxicities in several cancers. This study investigated whether BCMs could predict drug toxicity occurrence in advanced STS patients treated with eribulin.


This study included 23 advanced STS patients treated with eribulin between March 2016 and April 2018. BCMs were evaluated using a CT scan obtained within 1 month before or after treatment initiation. The relationship of BCMs and other clinical factors was evaluated and CART analysis used to develop classification models for risk groups of drug toxicity.


Sixteen patients (69.6%) experienced any grade 3/4 toxicity. Eleven patients (47.8%) developed G4 hematologic toxicity, which was significantly higher in those with low skeletal muscle gauge (SMG) (P = 0.02) and low pretreatment neutrophil count (P = 0.0002). Six patients (26.1%) had grade 3/4 non-hematologic toxicity, and was higher in those with low SMG (P = 0.004), and low serum albumin level (P = 0.02). Five patients with high BMI (P = 0.03) experienced febrile neutropenia (FN) and low pretreatment neutrophil count (P = 0.02). CART analysis classified three risk groups, and area under the receiver operating characteristic curve (AUROCC) was 0.92, 0.88, 0.92 in G4 hematologic AE, G3/4 non-hematologic AE, FN, respectively.


SMG is a significant predictive factor of eribulin drug toxicity in advanced STS patients. Risk classification of drug toxicity through combining predictive factors, could improve the therapeutic strategy used in chemotherapy.


Advanced soft tissue sarcoma Eribulin Body composition metrics Toxicity 



This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

All authors declare that there are no conflicts of interest relevant to this manuscript.


  1. 1.
    Clark MA, Fisher C, Judson I et al (2005) Soft-tissue sarcomas in adults. N Engl J Med 353:701–711CrossRefGoogle Scholar
  2. 2.
    Mastrangelo G, Coindre JM, Ducimetière F et al (2012) Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions. Cancer 118:5339–5348CrossRefGoogle Scholar
  3. 3.
    Stiller CA, Trama A, Serraino D et al (2013) Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project. Eur J Cancer 49:684–695CrossRefGoogle Scholar
  4. 4.
    Byerly S, Chopra S, Nassif NA et al (2016) The role of margins in extremity soft tissue sarcoma. J Surg Oncol 113:333–338CrossRefGoogle Scholar
  5. 5.
    Callegaro D, Miceli R, Bonvalot S et al (2016) Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft-tissue sarcomas of the extremities: a retrospective analysis. Lancet Oncol 17:671–680CrossRefGoogle Scholar
  6. 6.
    van der Graaf WT, Blay JY, Chawla SP et al (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879–1886CrossRefGoogle Scholar
  7. 7.
    Schöffski P, Chawla S, Maki RG et al (2016) Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 387:1629–1637CrossRefGoogle Scholar
  8. 8.
    Kawai A, Araki N, Sugiura H et al (2015) Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol 16:406–416CrossRefGoogle Scholar
  9. 9.
    Demetri GD, Chawla SP, von Mehren M et al (2009) Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol 27:4188–4196CrossRefGoogle Scholar
  10. 10.
    Smith JA, Wilson L, Azarenko O et al (2010) Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry 49:1331–1337CrossRefGoogle Scholar
  11. 11.
    Towle MJ, Salvato KA, Wels BF et al (2011) Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Res 71:496–505CrossRefGoogle Scholar
  12. 12.
    Dybdal-Hargreaves NF, Risinger AL, Mooberry SL (2015) Eribulin mesylate: mechanism of action of a unique microtubule-targeting agent. Clin Cancer Res 21:2445–2452CrossRefGoogle Scholar
  13. 13.
    Funahashi Y, Okamoto K, Adachi Y et al (2014) Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 105:1334–1342CrossRefGoogle Scholar
  14. 14.
    Yoshida T, Ozawa Y, Kimura T et al (2014) Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) states. Br J Cancer 110:1497–1505CrossRefGoogle Scholar
  15. 15.
    Schöffski P, Ray-Coquard IL, Cioffi A et al (2011) Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol 12:1045–1052CrossRefGoogle Scholar
  16. 16.
    Schöffski P, Chawla S, Maki R et al (2016) Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 387:1629–1637CrossRefGoogle Scholar
  17. 17.
    Kawai A, Araki N, Naito Y et al (2017) Phase 2 study of eribulin in patients with previously treated advanced or metastatic soft tissue sarcoma. Jpn J Clin Oncol 47(2):137–144CrossRefGoogle Scholar
  18. 18.
    Baracos VE, Arribas L (2018) Sarcopenic obesity: hidden muscle wasting and its impact for survival and complications of cancer therapy. Ann Oncol 1;29Google Scholar
  19. 19.
    Prado CM, Lieffers JR, McCargar LJ et al (2008) Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol 9(7):629–635CrossRefGoogle Scholar
  20. 20.
    Tan BH, Brammer K, Randhawa N et al (2015) Sarcopenia is associated with toxicity in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer. Eur J Surg Oncol 41(3):333–338CrossRefGoogle Scholar
  21. 21.
    Antoun S, Baracos VE, Birdsell L et al (2010) Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma. Ann Oncol 21(8):1594–1598CrossRefGoogle Scholar
  22. 22.
    Daly LE, Power DG, O’Reilly Á et al (2017) The impact of body composition parameters on ipilimumab toxicity and survival in patients with metastatic melanoma. Br J Cancer 116(3):310–317CrossRefGoogle Scholar
  23. 23.
    Shachar SS, Deal AM, Weinberg M et al (2017) Body composition as a predictor of toxicity in patients receiving anthracycline and taxane-based chemotherapy for early-stage breast cancer. Clin Cancer Res 23(14):3537–3543CrossRefGoogle Scholar
  24. 24.
    Kazemi-Bajestani SM, Mazurak VC, Baracos V (2016) Computed tomography-defined muscle and fat wasting are associated with cancer clinical outcomes. Semin Cell Dev Biol 54:2–10CrossRefGoogle Scholar
  25. 25.
    Prado CM, Baracos VE, McCargar LJ et al (2009) Sarcopenia as a determinant of chemotherapy toxicity and time to tumor progression in metastatic breast cancer patients receiving capecitabine treatment. Clin Cancer Res 15:2920–2926CrossRefGoogle Scholar
  26. 26.
    Weinberg M, Shachar S, Deal A et al (2016) Characterization of skeletal muscle and body mass indices in younger and older women with stage II and III breast cancer. J Am Geriatr Soc supplement:S86Google Scholar
  27. 27.
    Kwon WA, Oh TH, Lee JW et al (2014) Predictive factors for neutropenia after docetaxel-based systemic chemotherapy in Korean patients with castration- resistant prostate cancer. Asian Pac J Cancer Prev 15(8):3443–3446CrossRefGoogle Scholar
  28. 28.
    Kwon WA, Oh TH, Lee JW et al (2018) Factors that predict neutropenia in Korean patients with advanced urothelial cancer after cisplatin-based systemic chemotherapy. Urol J 15(4):168–172PubMedGoogle Scholar
  29. 29.
    Razzaghdoust A, Mofid B, Moghadam M (2018) Development of a simplified multivariable model to predict neutropenic complications in cancer patients undergoing chemotherapy. Support Care Cancer. (Epub ahead of print)CrossRefPubMedGoogle Scholar
  30. 30.
    Nishikawa M, Miyake H, Fujisawa M (2017) Identification of risk factors predicting febrile neutropenia in patients with metastatic germ cell tumors receiving cisplatin-based combination chemotherapy. Int J Urol 24(6):449–453CrossRefGoogle Scholar
  31. 31.
    Lyman GH, Dale DC, Friedberg J et al (2004) Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin Oncol 22:4302–4311CrossRefGoogle Scholar
  32. 32.
    Cullen MH, Billingham LJ, Gaunt CH et al (2007) Rational selection of patients for antibacterial prophylaxis after chemotherapy. J Clin Oncol 25:4821–4828CrossRefGoogle Scholar
  33. 33.
    Grabowski JP, Richter R, Rittmeister H et al (2018) Impact of body mass index (BMI) on chemotherapy-associated toxicity in ovarian cancer patients. A pooled analysis of the north-eastern german society of gynecological oncology (NOGGO) databank on 1213 patients. Nticancer Res 38(10):5853–5858CrossRefGoogle Scholar
  34. 34.
    Vincenzi B, Badalamenti G, Armento G et al (2018) Body mass index as a risk factor for toxicities in patients with advanced soft-tissue sarcoma treated with trabectedin. Oncology 95(1):1–7CrossRefGoogle Scholar
  35. 35.
    Kosaka T, Shinojima T, Morita S et al (2018) Prognostic significance of grade 3/4 neutropenia in Japanese prostate cancer patients treated with cabazitaxel. Cancer Sci 109(5):1570–1575CrossRefGoogle Scholar
  36. 36.
    Di Maio M, Gridelli C, Gallo C et al (2005) Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol 6:669–677CrossRefGoogle Scholar
  37. 37.
    Shitara K, Matsuo K, Takahari D et al (2009) Neutropaenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOX. Eur J Cancer 45:1757–1763CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2018

Authors and Affiliations

  • Hiroshi Kobayashi
    • 1
    Email author
  • Tomotake Okuma
    • 2
  • Hiroyuki Oka
    • 3
  • Koichi Okajima
    • 2
  • Yuki Ishibashi
    • 2
  • Liuzhe Zhang
    • 4
  • Toshihide Hirai
    • 1
  • Takahiro Ohki
    • 2
  • Yusuke Tsuda
    • 1
  • Masachika Ikegami
    • 1
  • Ryoko Sawada
    • 1
  • Yusuke Shinoda
    • 1
  • Toru Akiyama
    • 4
  • Hirotaka Kawano
    • 5
  • Takahiro Goto
    • 2
  • Sakae Tanaka
    • 1
  1. 1.Department of Orthopaedic Surgery, Faculty of MedicineThe University of Tokyo HospitalTokyoJapan
  2. 2.Department of Musculoskeletal OncologyTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalTokyoJapan
  3. 3.Department of Medical Research and Management for Musculoskeletal Pain, 22nd Century Medical & Research Center, Faculty of MedicineThe University of Tokyo HospitalTokyoJapan
  4. 4.Department of Orthopaedic Surgery, Saitama Medical CenterJichi Medical UniversitySaitamaJapan
  5. 5.Department of Orthopaedic Surgery, Faculty of MedicineUniversity of TeikyoTokyoJapan

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