Skip to main content
SpringerLink
Log in

New Frontiers in Transarterial Chemoembolization: Combination with Systemic Therapies

  • Chapter
  • First Online:
Transarterial Chemoembolization (TACE)

  • 101 Accesses

Abstract

Transarterial chemoembolization (TACE) is one of the treatment most frequently used in patients with liver cancer, in particular hepatocellular carcinoma (HCC). Although the survival of patients treated by TACE has markedly improved over the last decades, the prognosis remains poor. Systemic treatment of HCC has become the focus of intensive research with combination of immunotherapies, tyrosine kinase inhibitors and antiangiogenic drugs. TACE combined with systemic therapies, such as in particular immunotherapies, have the potential to improve outcomes. Here we present the rationale for such combination and provide an overview of clinical achievements and ongoing research in this field.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AFP:

Alpha-fetoprotein

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

HAIAT:

Hypoxia-activated intra-arterial therapy

HAL:

Hepatic arterial ligation

HAPs:

Hypoxia-activated prodrugs

HCC:

Hepatocellular carcinoma

HIF-1α:

Hypoxia-inducible factor-1α

HMGB1:

High-mobility group box 1

PD-1:

Programmed cell death 1 receptor

PD-L1:

Programmed cell death 1 ligand

PFS:

Progression-free survival

RAGE:

Receptor of advanced glycation end products

TAAs:

Tumor-associated antigens

TACE:

Transarterial chemoembolization

Th17:

Type 17 helper T cells

Tregs:

Regulatory T cells

TTP:

Time to progression

VEGF:

Vascular endothelial growth factor

References

  1. European Association for the Study of the Liver. Electronic address easl office easl office eu, European Association for the Study of the L. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236.

    Article  Google Scholar 

  2. Frilling A, Clift AK. Therapeutic strategies for neuroendocrine liver metastases. Cancer. 2015;121(8):1172–86.

    Article  CAS  PubMed  Google Scholar 

  3. Lencioni R, Aliberti C, de Baere T, Garcia-Monaco R, Narayanan G, O’Grady E, et al. Transarterial treatment of colorectal cancer liver metastases with irinotecan-loaded drug-eluting beads: technical recommendations. J Vasc Interv Radiol. 2014;25(3):365–9.

    Article  PubMed  Google Scholar 

  4. Albert M, Kiefer MV, Sun W, Haller D, Fraker DL, Tuite CM, et al. Chemoembolization of colorectal liver metastases with cisplatin, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol. Cancer. 2011;117(2):343–52.

    Article  CAS  PubMed  Google Scholar 

  5. Sahara S, Kawai N, Sato M, Tanaka T, Ikoma A, Nakata K, et al. Prospective evaluation of transcatheter arterial chemoembolization (TACE) with multiple anti-cancer drugs (epirubicin, cisplatin, mitomycin c, 5-fluorouracil) compared with TACE with epirubicin for treatment of hepatocellular carcinoma. Cardiovasc Interv Radiol. 2012;35(6):1363–71.

    Article  Google Scholar 

  6. Duran R, Chapiro J, Schernthaner RE, Geschwind JF. Systematic review of catheter-based intra-arterial therapies in hepatocellular carcinoma: state of the art and future directions. Br J Radiol. 2015;88(1052):20140564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46(3):474–81.

    Article  CAS  PubMed  Google Scholar 

  8. Takayasu K, Arii S, Ikai I, Kudo M, Matsuyama Y, Kojiro M, et al. Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis. AJR Am J Roentgenol. 2010;194(3):830–7.

    Article  PubMed  Google Scholar 

  9. Degrauwe N, Hocquelet A, Digklia A, Schaefer N, Denys A, Duran R. Theranostics in interventional oncology: versatile carriers for diagnosis and targeted image-guided minimally invasive procedures. Front Pharmacol. 2019;10:450.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lencioni R, de Baere T, Soulen MC, Rilling WS, Geschwind JF. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology. 2016;64(1):106–16.

    Article  CAS  PubMed  Google Scholar 

  11. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  12. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Poon RT, Lau C, Yu WC, Fan ST, Wong J. High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: a prospective study. Oncol Rep. 2004;11(5):1077–84.

    CAS  PubMed  Google Scholar 

  14. Sergio A, Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A, et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol. 2008;103(4):914–21.

    Article  PubMed  Google Scholar 

  15. Shim JH, Park JW, Kim JH, An M, Kong SY, Nam BH, et al. Association between increment of serum VEGF level and prognosis after transcatheter arterial chemoembolization in hepatocellular carcinoma patients. Cancer Sci. 2008;99(10):2037–44.

    CAS  PubMed  Google Scholar 

  16. Wang B, Xu H, Gao ZQ, Ning HF, Sun YQ, Cao GW. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol. 2008;49(5):523–9.

    Article  CAS  PubMed  Google Scholar 

  17. Ronald J, Nixon AB, Marin D, Gupta RT, Janas G, Chen W, et al. Pilot evaluation of angiogenesis Signaling factor response after transcatheter arterial embolization for hepatocellular carcinoma. Radiology. 2017;285(1):311–8.

    Article  PubMed  Google Scholar 

  18. Bize P, Duran R, Fuchs K, Dormond O, Namur J, Decosterd LA, et al. Antitumoral effect of sunitinib-eluting beads in the rabbit VX2 tumor model. Radiology. 2016;280(2):425–35.

    Article  PubMed  Google Scholar 

  19. Duran R, Namur J, Pascale F, Czuczman P, Bascal Z, Kilpatrick H, et al. Vandetanib-eluting radiopaque beads: pharmacokinetics, safety, and efficacy in a rabbit model of liver cancer. Radiology. 2019;293(3):695–703.

    Article  PubMed  Google Scholar 

  20. Vasudev NS, Reynolds AR. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis. 2014;17(3):471–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4(6):437–47.

    Article  CAS  PubMed  Google Scholar 

  22. Scheffer SR, Nave H, Korangy F, Schlote K, Pabst R, Jaffee EM, et al. Apoptotic, but not necrotic, tumor cell vaccines induce a potent immune response in vivo. Int J Cancer. 2003;103(2):205–11.

    Article  CAS  PubMed  Google Scholar 

  23. Festjens N, Vanden Berghe T, Vandenabeele P. Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta. 2006;1757(9–10):1371–87.

    Article  CAS  PubMed  Google Scholar 

  24. Gamrekelashvili J, Kruger C, von Wasielewski R, Hoffmann M, Huster KM, Busch DH, et al. Necrotic tumor cell death in vivo impairs tumor-specific immune responses. J Immunol. 2007;178(3):1573–80.

    Article  CAS  PubMed  Google Scholar 

  25. Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005;202(12):1691–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.

    Article  CAS  PubMed  Google Scholar 

  27. Kim MJ, Jang JW, Oh BS, Kwon JH, Chung KW, Jung HS, et al. Change in inflammatory cytokine profiles after transarterial chemotherapy in patients with hepatocellular carcinoma. Cytokine. 2013;64(2):516–22.

    Article  CAS  PubMed  Google Scholar 

  28. Kohles N, Nagel D, Jungst D, Stieber P, Holdenrieder S. Predictive value of immunogenic cell death biomarkers HMGB1, sRAGE, and DNase in liver cancer patients receiving transarterial chemoembolization therapy. Tumour Biol. 2012;33(6):2401–9.

    Article  CAS  PubMed  Google Scholar 

  29. Ayaru L, Pereira SP, Alisa A, Pathan AA, Williams R, Davidson B, et al. Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization. J Immunol Baltim Md 1950. 2007;178(3):1914–22.

    CAS  Google Scholar 

  30. Nobuoka D, Motomura Y, Shirakawa H, Yoshikawa T, Kuronuma T, Takahashi M, et al. Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes. Int J Oncol. 2012;40(1):63–70.

    CAS  PubMed  Google Scholar 

  31. Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology. 2014;59(4):1415–26.

    Article  CAS  PubMed  Google Scholar 

  32. Mizukoshi E, Nakamoto Y, Arai K, Yamashita T, Sakai A, Sakai Y, et al. Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma. Hepatology. 2011;53(4):1206–16.

    Article  CAS  PubMed  Google Scholar 

  33. Li F, Guo Z, Lizee G, Yu H, Wang H, Si T. Clinical prognostic value of CD4+CD25+FOXP3+regulatory T cells in peripheral blood of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma patients. Clin Chem Lab Med. 2014;52(9):1357–65.

    Article  CAS  PubMed  Google Scholar 

  34. Liao J, Xiao J, Zhou Y, Liu Z, Wang C. Effect of transcatheter arterial chemoembolization on cellular immune function and regulatory T cells in patients with hepatocellular carcinoma. Mol Med Rep. 2015;12(4):6065–71.

    Article  CAS  PubMed  Google Scholar 

  35. Liao Y, Wang B, Huang ZL, Shi M, Yu XJ, Zheng L, et al. Increased circulating Th17 cells after transarterial chemoembolization correlate with improved survival in stage III hepatocellular carcinoma: a prospective study. PLoS One. 2013;8(4):e60444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  37. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.

    Article  CAS  PubMed  Google Scholar 

  38. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905.

    Article  CAS  PubMed  Google Scholar 

  39. Lencioni R, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L, et al. GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and of its treatment with sorafeNib): second interim analysis. Int J Clin Pract. 2014;68(5):609–17.

    Article  CAS  PubMed  Google Scholar 

  40. Geschwind JF, Kudo M, Marrero JA, Venook AP, Chen XP, Bronowicki JP, et al. TACE treatment in patients with sorafenib-treated unresectable hepatocellular carcinoma in clinical practice: final analysis of GIDEON. Radiology. 2016;279(2):630–40.

    Article  PubMed  Google Scholar 

  41. Cai R, Song R, Pang P, Yan Y, Liao Y, Zhou C, et al. Transcatheter arterial chemoembolization plus sorafenib versus transcatheter arterial chemoembolization alone to treat advanced hepatocellular carcinoma: a meta-analysis. BMC Cancer. 2017;17(1):714.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wang G, Liu Y, Zhou SF, Qiu P, Xu L, Wen P, et al. Sorafenib combined with transarterial chemoembolization in patients with hepatocellular carcinoma: a meta-analysis and systematic review. Hepatol Int. 2016;10(3):501–10.

    Article  PubMed  Google Scholar 

  43. Li L, Zhao W, Wang M, Hu J, Wang E, Zhao Y, et al. Transarterial chemoembolization plus sorafenib for the management of unresectable hepatocellular carcinoma: a systematic review and meta-analysis. BMC Gastroenterol. 2018;18(1):138.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lencioni R, Llovet JM, Han G, Tak WY, Yang J, Guglielmi A, et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol. 2016;64(5):1090–8.

    Article  CAS  PubMed  Google Scholar 

  45. Kudo M, Imanaka K, Chida N, Nakachi K, Tak WY, Takayama T, et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer. 2011;47(14):2117–27.

    Article  CAS  PubMed  Google Scholar 

  46. Kudo M, Han G, Finn RS, Poon RT, Blanc JF, Yan L, et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology. 2014;60(5):1697–707.

    Article  CAS  PubMed  Google Scholar 

  47. Kudo M, Cheng AL, Park JW, Park JH, Liang PC, Hidaka H, et al. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet Gastroenterol Hepatol. 2018;3(1):37–46.

    Article  PubMed  Google Scholar 

  48. Pinter M, Ulbrich G, Sieghart W, Kolblinger C, Reiberger T, Li S, et al. Hepatocellular carcinoma: a phase II randomized controlled double-blind trial of transarterial chemoembolization in combination with biweekly intravenous administration of bevacizumab or a placebo. Radiology. 2015;277(3):903–12.

    Article  PubMed  Google Scholar 

  49. Park JW, Kim YJ, Kim DY, Bae SH, Paik SW, Lee YJ, et al. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial. J Hepatol. 2019;70(4):684–91.

    Article  CAS  PubMed  Google Scholar 

  50. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kelley RK, Sangro B, Harris W, Ikeda M, Okusaka T, Kang YK, et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study. J Clin Oncol. 2021;39(27):2991–3001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shi L, Wang J, Ding N, Zhang Y, Zhu Y, Dong S, et al. Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy. Nat Commun. 2019;10(1):5421.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017;66(3):545–51.

    Article  CAS  PubMed  Google Scholar 

  54. Pinato DJ, Cole T, Bengsch B, Tait P, Sayed AA, Abomeli F, et al. 750P—a phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL. Ann Oncol. 2019;30:v288.

    Article  Google Scholar 

  55. Marabelle A, Tselikas L, de Baere T, Houot R. Intratumoral immunotherapy: using the tumor as the remedy. Ann Oncol. 2017;28:xii33-43.

    Article  Google Scholar 

  56. Marabelle A, Andtbacka R, Harrington K, Melero I, Leidner R, de Baere T, et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann Oncol. 2018;29(11):2163–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tselikas L, Champiat S, Sheth RA, Yevich S, Ammari S, Deschamps F, et al. Interventional radiology for local immunotherapy in oncology. Clin Cancer Res. 2021;27(10):2698–705.

    Article  PubMed  Google Scholar 

  58. Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021;27(1):152–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sato T, Eschelman DJ, Gonsalves CF, Terai M, Chervoneva I, McCue PA, et al. Immunoembolization of malignant liver tumors, including uveal melanoma, using granulocyte-macrophage colony-stimulating factor. J Clin Oncol. 2008;26(33):5436–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yamamoto A, Chervoneva I, Sullivan KL, Eschelman DJ, Gonsalves CF, Mastrangelo MJ, et al. High-dose immunoembolization: survival benefit in patients with hepatic metastases from Uveal Melanoma1. Radiology. 2009;252(1):290–8.

    Article  PubMed  Google Scholar 

  61. Valsecchi ME, Terai M, Eschelman DJ, Gonsalves CF, Chervoneva I, Shields JA, et al. Double-blinded, randomized phase II study using embolization with or without granulocyte-macrophage colony-stimulating factor in uveal melanoma with hepatic metastases. J Vasc Interv Radiol. 2015;26(4):523–32 e2.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393–410.

    Article  CAS  PubMed  Google Scholar 

  63. Li Y, Zhao L, Li XF. The hypoxia-activated prodrug TH-302: exploiting hypoxia in cancer therapy. Front Pharmacol. 2021;12:636892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Duran R, Mirpour S, Pekurovsky V, Ganapathy-Kanniappan S, Brayton CF, Cornish TC, et al. Preclinical benefit of hypoxia-activated intra-arterial therapy with evofosfamide in liver cancer. Clin Cancer Res. 2017;23(2):536–48.

    Article  CAS  PubMed  Google Scholar 

  65. Lin WH, Yeh SH, Yeh KH, Chen KW, Cheng YW, Su TH, et al. Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice. Proc Natl Acad Sci USA. 2016;113(42):11937–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Abi-Jaoudeh N, Dayyani F, Chen PJ, Fernando D, Fidelman N, Javan H, et al. Phase I trial on arterial embolization with hypoxia activated tirapazamine for unresectable hepatocellular carcinoma. J Hepatocell Carcinoma. 2021;8:421–34.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiology and Interventional Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

    Rafael Duran

  2. Département d’Anesthésie, Chirurgie et Interventionnel (DACI), Gustave Roussy, Villejuif, France

    Thierry de Baere & Lambros Tselikas

  3. Gustave Roussy Cancer Campus, Université Paris Saclay, Saint-Aubin, France

    Thierry de Baere

  4. Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Gustave Roussy, Villejuif, France

    Lambros Tselikas

Authors
  1. Rafael Duran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thierry de Baere
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lambros Tselikas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rafael Duran .

Editor information

Editors and Affiliations

  1. Vascular and Interventional Radiology, Azienda Ospedaliera Universitaria Policlinico Umberto I, Sapienza University of Rome, ROMA, Roma, Italy

    Pierleone Lucatelli

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Duran, R., de Baere, T., Tselikas, L. (2023). New Frontiers in Transarterial Chemoembolization: Combination with Systemic Therapies. In: Lucatelli, P. (eds) Transarterial Chemoembolization (TACE) . Springer, Cham. https://doi.org/10.1007/978-3-031-36261-3_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-36261-3_13

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-36260-6

  • Online ISBN: 978-3-031-36261-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation