Skip to main content
SpringerLink
Log in

Promising New Molecular Targeted Therapies in Head and Neck Cancer

  • Leading Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Despite advances in multimodality therapies for the treatment of squamous cell carcinoma of the head and neck (SCCHN), survival rates, functional outcomes and toxicities of therapy remain poor. The recognition of the prognostic value of human papillomavirus (HPV) status, and the advent of biologically targeted therapies with potential for decreased toxicities and increased selectivity, represent significant developments in our understanding of SCCHN. Targeted agents currently approved or under investigation for SCCHN include epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab, panitumumab, zalutumumab, nimotuzumab), EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib, afatanib, dacomitinib), vascular endothelial growth factor receptor (VEGFR) inhibitors (bevacizumab, sorafenib, sunitinib, vandetanib) and various inhibitors of other pathways and targets, including phosphatidylinositol 3′ kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), MET and insulin-like growth factor receptor (IGF-1R). On-going clinical trials are evaluating these emerging agents and their combinations in the treatment of SCCHN.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  2. Westra WH. The changing face of head and neck cancer in the 21st century: the impact of HPV on the epidemiology and pathology of oral cancer. Head Neck Pathol. 2009;3(1):78–81.

    Article  PubMed  Google Scholar 

  3. Gillison ML. Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity. Semin Oncol. 2004;31:744–54.

    Article  PubMed  Google Scholar 

  4. Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer. 2007;110:1429–35.

    Article  PubMed  Google Scholar 

  5. Gasco M, Crook T. The p53 network in head and neck cancer. Oral Oncol. 2003;39:222–31.

    Article  PubMed  CAS  Google Scholar 

  6. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.

    Article  PubMed  CAS  Google Scholar 

  7. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261–9.

    Article  PubMed  CAS  Google Scholar 

  8. Monnerat C, Faivre S, Temam S, Bourhis J, Raymond E. End points for new agents in induction chemotherapy for locally advanced head and neck cancers. Ann Oncol. 2002;13:995–1006.

    Article  PubMed  CAS  Google Scholar 

  9. Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer. 2005;114:806–16.

    Article  PubMed  CAS  Google Scholar 

  10. Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2006;24:2644–52.

    Article  PubMed  CAS  Google Scholar 

  11. Cohen EE, Lingen MW, Vokes EE. The expanding role of systemic therapy in head and neck cancer. J Clin Oncol. 2004;22:1743–52.

    Article  PubMed  Google Scholar 

  12. Agulnik M. New approaches to EGFR inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN). Med Oncol. 2012;29(4):2481–91.

    Article  PubMed  CAS  Google Scholar 

  13. Holbro T, Civenni G, Hynes NE. The ErbB receptors and their role in cancer progression. Exp Cell Res. 2003;284:99–110.

    Article  PubMed  CAS  Google Scholar 

  14. Hynes NE, Horsch K, Olayioye MA, Badache A. The ErbB receptor tyrosine family as signal integrators. Endocr Relat Cancer. 2001;8:151–9.

    Article  PubMed  CAS  Google Scholar 

  15. Rocha-Lima CM, Soares HP, Raez LE, Singal R. EGFR targeting of solid tumors. Cancer Control. 2007;14:295–304.

    PubMed  Google Scholar 

  16. Ogiso H, Ishitani R, Nureki O, et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell. 2002;110:775–87.

    Article  PubMed  CAS  Google Scholar 

  17. Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002;110:669–72.

    Article  PubMed  CAS  Google Scholar 

  18. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    Article  PubMed  CAS  Google Scholar 

  19. Kruger JS, Reddy KB. Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells. Mol Cancer Res. 2003;1:801–9.

    PubMed  CAS  Google Scholar 

  20. Masuda M, Toh S, Koike K, et al. The roles of JNK1 and Stat3 in the response of head and neck cancer cell lines to combined treatment with all-trans-retinoic acid and 5-fluorouracil. Jpn J Cancer Res. 2002;93:329–39.

    Article  PubMed  CAS  Google Scholar 

  21. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.

    Article  PubMed  CAS  Google Scholar 

  22. Ellerbroek SM, Halbleib JM, Benavidez M, et al. Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. Cancer Res. 2001;61:1855–61.

    PubMed  CAS  Google Scholar 

  23. Shtiegman K, Yarden Y. The role of ubiquitylation in signaling by growth factors: implications to cancer. Semin Cancer Biol. 2003;13:29–40.

    Article  PubMed  CAS  Google Scholar 

  24. Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist. 2002;7(Suppl. 4):31–9.

    Article  PubMed  CAS  Google Scholar 

  25. Cruz JJ, Ocana A, Del Barco E, Pandiella A. Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer. Ann Oncol. 2007;18:421–30.

    Article  PubMed  CAS  Google Scholar 

  26. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37(Suppl. 4):S9–15.

    Article  PubMed  CAS  Google Scholar 

  27. Zimmermann M, Zouhair A, Azria D, Ozsahin M. The epidermal growth factor receptor (EGFR) in head and neck cancer: its role and treatment implications. Radiat Oncol. 2006;1:11.

    Article  PubMed  Google Scholar 

  28. Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res. 1984;44:1002–7.

    PubMed  CAS  Google Scholar 

  29. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–78.

    Article  PubMed  CAS  Google Scholar 

  30. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21–8.

    Article  PubMed  CAS  Google Scholar 

  31. Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol. 2006;24:1072–8.

    Article  PubMed  CAS  Google Scholar 

  32. Ang KK, Zhang QE, Rosenthal DI, et al. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III–IV head and neck squamous cell carcinomas (HNC) [abstract no. 5500]. J Clin Oncol. 2011;29(Suppl.).

  33. Lefebvre J, Pointreau Y, Rolland F, et al. Sequential chemoradiotherapy (SRCT) for larynx preservation (LP): Results of the randomized phase II TREMPLIN study [abstract no. 5501]. J Clin Oncol. 2011;29(Suppl.).

  34. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005;23:8646–54.

    Article  PubMed  Google Scholar 

  35. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27.

    Article  PubMed  CAS  Google Scholar 

  36. Vermorken JB, Peyrade F, Krauss J, et al. Cilengitide with cetuximab, cisplatin, and 5-FU in R/M SCCHN: the ADVANTAGE phase II trial [abstract no. 5516]. J Clin Oncol. 2012;30(Suppl.).

  37. Guigay J, Fayette J, Dillies AF, et al. Cetuximab, docetaxel, and cisplatin (TPEx) as first line treatment in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: Final results of phase II trial GORTEC 2008-03 [abstract no. 5505]. J Clin Oncol. 2012;30(Suppl.).

  38. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25:2171–7.

    Article  PubMed  CAS  Google Scholar 

  39. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5568–77.

    Article  PubMed  CAS  Google Scholar 

  40. Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5578–87.

    Article  PubMed  CAS  Google Scholar 

  41. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol. 2001;38:17–23.

    Article  PubMed  CAS  Google Scholar 

  42. Foon KA, Yang XD, Weiner LM, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys. 2004;58:984–90.

    Article  PubMed  CAS  Google Scholar 

  43. Giralt J, Fortin A, Mesia R, et al. A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients with unresected, locally advanced squamous cell carcinoma of the head and neck [abstract no. 5502]. J Clin Oncol. 2012;30(Suppl.).

  44. Vermorken JB, Stohlmacher J, Davidenko I, et al. Primary efficacy and safety results of SPECTRUM, a phase 3 trial in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without panitumumab [abstract no. LBA26]. Ann Oncol 2010;21(Suppl. 8).

  45. Stoehlmacher-Williams J, Villanueva C, Foa P, et al. Safety and efficacy of panitumumab in HPV-positive and HPV-negative recurrent/metastatic squamous cell carcinoma of the head and neck: analysis of the global phase III SPECTRUM trial [abstract no. 5504]. J Clin Oncol. 2012;30(Suppl.).

  46. Machiels JP, Subramanian S, Ruzsa A, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol. 2011;12:333–43.

    Article  PubMed  CAS  Google Scholar 

  47. Ramakrishnan, Eswaraiah A, Crombet T, et al. Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin. mAbs. 2009;1(1):41–8.

    Article  PubMed  Google Scholar 

  48. Babu KG, Viswanath L, Reddy BK, et al. An open-label, randomized, study of h-R3mAb (nimotuzumab) in patients with advanced (stage III or IVa) squamous cell carcinoma of head and neck (SCCHN): four-year survival results from a phase IIb study [abstract no. 5530]. J Clin Oncol. 2010;28(Suppl.).

  49. Rodriguez MO, Rivero TC, del Castillo Bahi R, et al. Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck. Cancer Biol Ther. 2010;9(5):343–9.

    Article  PubMed  CAS  Google Scholar 

  50. Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol. 2003;21:1980–7.

    Article  PubMed  CAS  Google Scholar 

  51. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected; published erratum appears in J Clin Oncol 2009;27(20):3410]. J Clin Oncol. 2009;27(11):1864–71.

    Article  PubMed  CAS  Google Scholar 

  52. Argiris A, Ghebremichael M, Gilbert J, et al. A phase III randomized, placebo controlled trial of docetaxel (D) with or without gefitinib (G) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): a trial of the Eastern cooperative oncology group (ECOG) [abstract no. 6011]. J Clin Oncol. 2009;27(Suppl):15.

    Google Scholar 

  53. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004;22:77–85.

    Article  PubMed  CAS  Google Scholar 

  54. Siu LL, Soulieres D, Chen EX, et al. Phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Princess Margaret Hospital phase II consortium and National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol. 2007;25:2178–83.

    Article  PubMed  CAS  Google Scholar 

  55. Kim ES, Kies, Glisson BS, et al. Final results of a phase II study of erlotinib, docetaxel and cisplatin in patients with recurrent/metastatic head and neck cancer. J Clin Oncol 2007 ASCO Ann Meet Proc Part I. 2007;25:6013.

    Google Scholar 

  56. Harari PM, Allen GW, Bonner JA. Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol. 2007;25:4057–65.

    Article  PubMed  CAS  Google Scholar 

  57. Harrington KJ, Berrier A, Robinson M, et al. Phase II study of oral lapatinib, a dual tyrosine kinase inhibitor, combined with CRT in patients with locally advanced, unresected SCCHN [abstract no. 5505]. J Clin Oncol. 2010;28:15 Suppl.

    Google Scholar 

  58. Del Campo JM, Hitt R, Sebastian P, et al. Effects of lapatinib monotherapy: results of a randomised phase II study in therapy naive patients with locally advance SCCHN. Br J Cancer. 2011;105:618–27.

    Article  PubMed  Google Scholar 

  59. Abidoye OO, Cohen EE, Wong SJ, et al. A phase II study of lapatinib (GW572016) in recurrent /metastatic (R/M) squamous cell carcinoma of head and neck (SCCHN) [abstract no. 5568]. J Clin Oncol. 2006;24:18 Suppl.

    Google Scholar 

  60. Seiwert TY, Fayette J, Del Campo JM, et al. Updated results of a randomized, open-label phase II study exploring BIBW 2992 versus cetuximab in patients with platinum refractory metastatic/recurrent head and neck cancer (SCCHN) [abstract no. 1010PD]. Ann Oncol. 2010;21(Suppl):8.

    Google Scholar 

  61. Siu LL, Hotte SJ, Laurie SA, et al. Phase II trial of the irreversible oral pan-human EGF receptor (HER) inhibitor PF-00299804 (PF) as first-line treatment in recurrent and/or metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN) [abstract no. 5561]. J Clin Oncol. 2011;29 Suppl.

  62. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82:4–6.

    Article  PubMed  CAS  Google Scholar 

  63. Zhong H, Bowen JP. Molecular design and clinical development of VEGFR kinase inhibitors. Curr Top Med Chem. 2007;7:1379–93.

    Article  PubMed  CAS  Google Scholar 

  64. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376:62–6.

    Article  PubMed  CAS  Google Scholar 

  65. Kyzas PA, Cunha IW, Ioannidis JP. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res. 2005;11:1434–40.

    Article  PubMed  CAS  Google Scholar 

  66. Kyzas PA, Stefanou D, Batistatou A, Agnantis NJ. Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2. Mod Pathol. 2005;18:485–94.

    Article  PubMed  CAS  Google Scholar 

  67. Argiris A, Karamouzis MV, Gooding WE, et al. Phase II trial of pemetrexed and bevacizumab in patients with recurrent or metastatic head and neck cancer. J Clin Oncol. 2011;29:1140–5.

    Article  PubMed  CAS  Google Scholar 

  68. Cohen EE, Davis DW, Karrison TG, et al. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol. 2009;10:247–57.

    Article  PubMed  CAS  Google Scholar 

  69. Argiris A, Kotsakis AP, Kim S, et al. Phase II trial of cetuximab (C) and bevacizumab (B) in recurrent or metastatic squamous cell carcinoma of the head and neck: final results [abstract no. 5564]. J Clin Oncol. 2011;29:Suppl.

  70. Williamson SK, Moon J, Huang CH, et al. Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group Study S0420. J Clin Oncol. 2010;28:3330–5.

    Article  PubMed  CAS  Google Scholar 

  71. Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol. 2007;25:3766–73.

    Article  PubMed  CAS  Google Scholar 

  72. Blumenschein GR, Glisson BS, Lu C, et al. Final results of a phase II study of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic or recurrent SCCHN [abstract no. 5592]. J Clin Oncol. 2012;30:Suppl.

  73. Eder JP, Shapiro GI, Appleman LJ, et al. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin Cancer Res. 2010;16:3507–16.

    Article  PubMed  CAS  Google Scholar 

  74. Seiwert T, Sarantopoulos J, Kallender H, McCallum S, Keer HN, Blumenschein G Jr. Phase II trial of single-agent foretinib (GSK1363089) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Investig New Drugs. Epub 24 Aug 2012.

  75. Bähr C, Groner B. The IGF-1 receptor and its contributions to metastatic tumor growth-novel approaches to the inhibition of IGF-1R function. Growth Factors. 2005;23(1):1–14.

    Article  PubMed  Google Scholar 

  76. Adams TE, Epa VC, Garrett TP, Ward CW. Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci. 2000;57:1050–93.

    Article  PubMed  CAS  Google Scholar 

  77. Barnes CJ, Ohshiro K, Rayala SK, El-Naggar AK, Kumar R. Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res. 2007;13:4291–9.

    Article  PubMed  CAS  Google Scholar 

  78. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–18.

    Article  PubMed  CAS  Google Scholar 

  79. Mitsiades CS, Mitsiades N. Treatment of hematologic malignancies and solid tumors by inhibiting IGF receptor signaling. Expert Rev Anticancer Ther. 2005;5:487–99.

    Article  PubMed  CAS  Google Scholar 

  80. Larsson O, Girnita A, Girnita L. Role of insulin-like growth factor 1 receptor signalling in cancer. Br J Cancer. 2007;96 suppl.:R2–6.

    PubMed  Google Scholar 

  81. Machiels JP, Henry S, Zanetta S, Kaminsky MC, Michoux N, Rommel D, Schmitz S, Bompas E, Dillies AF, Faivre S, Moxhon A, Duprez T, Guigay J. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006–01. J Clin Oncol. 2010;28(1):21–8.

    Article  PubMed  CAS  Google Scholar 

  82. Choong NW, Kozloff M, Taber D, Hu HS, Wade J 3rd, Ivy P, Karrison TG, Dekker A, Vokes EE, Cohen EE. Phase II study of sunitinib malate in head and neck squamous cell carcinoma. Investig New Drugs. 2010;28(5):677–83.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Northwestern University, 676 N. St. Clair, Suite 850, Chicago, IL, 60611, USA

    Kelly Dorsey & Mark Agulnik

Authors
  1. Kelly Dorsey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark Agulnik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark Agulnik.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dorsey, K., Agulnik, M. Promising New Molecular Targeted Therapies in Head and Neck Cancer. Drugs 73, 315–325 (2013). https://doi.org/10.1007/s40265-013-0025-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-013-0025-3

Keywords

Search

Navigation