Advertisement

A phase 1 trial of Vorinostat in combination with concurrent chemoradiation therapy in the treatment of advanced staged head and neck squamous cell carcinoma

  • Theodoros N. TeknosEmail author
  • J. Grecula
  • A. Agrawal
  • M. O. Old
  • E. Ozer
  • R. Carrau
  • S. Kang
  • J. Rocco
  • D. Blakaj
  • V. Diavolitsis
  • B. Kumar
  • P. Kumar
  • Q. Pan
  • M. Palettas
  • L. Wei
  • R. Baiocchi
  • P. Savvides
PHASE I STUDIES
  • 45 Downloads

Summary

Purpose Vorinostat is a potent HDAC inhibitor that sensitizes head and neck squamous cell carcinoma (HNSCC) to cytotoxic therapy while sparing normal epithelium. The primary objective of this Phase I study was to determine the maximally tolerated dose (MTD) and safety of Vorinostat in combination with standard chemoradiation therapy treatment in HNSCC. Patients and Methods Eligible patients had pathologically confirmed Stage III, IVa, IVb HNSCC, that was unresectable or borderline resectable involving the larynx, hypopharynx, nasopharynx, and oropharynx. Vorinostat was administered at the assigned dosage level (100-400 mg, three times weekly) in a standard 3 + 3 dose escalation design. Vorinostat therapy began 1 week prior to initiation of standard, concurrent chemoradiation therapy and continued during the entire course of therapy. Results Twenty six patients met eligibility criteria and completed the entire protocol. The primary tumor sites included tonsil (12), base of tongue (9), posterior pharyngeal wall (1), larynx (4) and hypopharynx (3). Of the 26 patients, 17 were HPV-positive and 9 were HPV-negative. The MTD of Vorinostat was 300 mg administered every other day. Anemia (n = 23/26) and leukopenia (n = 20/26) were the most commonly identified toxicities. The most common Grade3/4 events included leukopenia (n = 11) and lymphopenia (n = 17). No patient had Grade IV mucositis, dermatitis or xerostomia. The median follow time was 33.8 months (range 1.6–82.9 months). Twenty four of 26 (96.2%) patients had a complete response to therapy. Conclusion Vorinostat in combination with concurrent chemoradiation therapy is a safe and highly effective treatment regimen in HNSCC. There was a high rate of complete response to therapy with toxicity rates comparable, if not favorable to existing therapies. Further investigation in Phase II and III trials is strongly recommended.

Keywords

Head and neck cancer Oropharyngeal cancer Chemoradiation therapy Organ preservation Phase I trial in advance stage head and neck cancer Histone deacetylase inhibitors in head and neck cancer HPV-related head and neck cancer 

Notes

Acknowledgements

This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Merck & Co., Inc.

Funding

This study was funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Merck & Co., Inc.

Compliance and ethical standards

Conflict of interest

All authors declare that there are no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Leemans CR, Braakhuis BJM, Brakenhoff RH (2011) The molecular biology of head and neck cancer. Nat Rev Cancer 11(1):9–22CrossRefGoogle Scholar
  2. 2.
    Mehanna H, Paleri V, West CML, Nutting C (2010) Head and neck cancer-part 1: epidemiology, presentation, and prevention. BMJ 341:c4684CrossRefGoogle Scholar
  3. 3.
    Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R, Jemal A (2016) Cancer treatment and survivorship statistics. Cancer J Clin 66:271–289CrossRefGoogle Scholar
  4. 4.
    Chaturvedi AK, Graubard BI, Broutian T, Pickard RKL, Tong ZY, Xiao W, Kahle L, Gillison ML (2015) NHANES 2009-2012 findings: association of sexual behaviors with higher prevalence of oral oncogenic human papillomavirus infections in U.S. men. Cancer Res 75:2468–2477CrossRefGoogle Scholar
  5. 5.
    Kalavrezos N, Bhandari R (2010) Current trends and future perspectives in the surgical management of oral cancer. Oral Oncol 46:429–432CrossRefGoogle Scholar
  6. 6.
    Edwards BK, Brown ML, Wingo PA et al (2005) Annual report to the nation on the status of cancer, 1975–2002, featuring population based trends in cancer treatment. J Natl Cancer Inst. Oct 5 97(19):1407–1427CrossRefGoogle Scholar
  7. 7.
    Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24–35CrossRefGoogle Scholar
  8. 8.
    Carvalho AL, Hishimoto IN, Califano JA et al (2005) 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 114:806–881CrossRefGoogle Scholar
  9. 9.
    Preuss SF, Quante G, Semrau R, Mueller RP, Klussmann JP, Guntinas-Lichius O (2007) An analysis of surgical complications, morbidity, and cost calculation in patients undergoing multimodal treatment for operable oropharyngeal carcinoma. Laryngoscope 117(1):101–105CrossRefGoogle Scholar
  10. 10.
    Sundaram K, Schwartz J, Har-El G et al (2005) Carcinoma of the oropharynx: factors affecting outcome. Laryngoscope 115(9):1536–1542CrossRefGoogle Scholar
  11. 11.
    Wolf GT, Fisher SG, Hong WK et al (1991) Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer: the department of veterans affairs laryngeal cancer study group. N Engl J Med 324:1685–1690CrossRefGoogle Scholar
  12. 12.
    Urba S, Wolf G, Eisbruch A, Worden F, Lee J, Bradford C, Teknos T, Chepeha D, Prince M, Hogikyan N, Taylor J (2006) Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: a new treatment paradigm. J Clin Oncol 24:593–598CrossRefGoogle Scholar
  13. 13.
    Worden FP, Kumar B, Lee JS et al (2008) Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol 26(19):3138–3146CrossRefGoogle Scholar
  14. 14.
    Adelstein DJ, Saxton JP, Lavertu P, Rybicki LA, Esclamado RM, Wood BG, Strome M, Carroll MA (2002) Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer with hyperfractionated radiation and concurrent chemotherapy. J Clin Oncol 20:1405–1410CrossRefGoogle Scholar
  15. 15.
    Garden AS, Harris J, Vokes EE, Forastiere AA, Ridge JA, Jones C, Horwitz EM, Glisson BS, Nabell L, Cooper JS, Demas W, Gore E (2004) Preliminary results of radiation therapy oncology group 9703: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol 22(14):2856–2864CrossRefGoogle Scholar
  16. 16.
    Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, Bergerot P, Rhein B, Tortochaux J, Calais G (2004 Jan 1) Final results of the 94-01 French head and neck oncology and radiotherapy group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. Clin Oncol 22(1):69–76 Epub 2003 Dec 2Google Scholar
  17. 17.
    Machtay M, Moughan J, Trotti A, Garden AS, Weber RS, Cooper JS, Forastiere A, Ang KK (2008) Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 26:3582–3589CrossRefGoogle Scholar
  18. 18.
    Hrzenjak A, Moinfar F, Kremser ML, Strohmeier B, Staber PB, Zatloukal K, Denk H (2006) Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells. Mol Cancer Ther 5:2203–2210CrossRefGoogle Scholar
  19. 19.
    Huang BH, Laban M, Leung CH et al (2005) Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ 12:395–404CrossRefGoogle Scholar
  20. 20.
    Westendorf JJ, Zaidi SK, Cascino JE, Kahler R, van Wijnen AJ, Lian JB, Yoshida M, Stein GS, Li X (2002) Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter. Mol Cell Biol 22:7982–7992CrossRefGoogle Scholar
  21. 21.
    Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Pérez-Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, Colomer D, Piris MÁ, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400CrossRefGoogle Scholar
  22. 22.
    Park SY, Jun JA, Jeong KJ et al (2011) Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer. Oncol Rep 25:1677–1168PubMedGoogle Scholar
  23. 23.
    Senese S, Zaragoza K, Minardi S et al (2007) Role for histone deacetylase 1 in human tumor cell proliferation. Mol Cell Biol 27:47844795CrossRefGoogle Scholar
  24. 24.
    Oehme I, Deubzer HE, Wegener D, Pickert D, Linke JP, Hero B, Kopp-Schneider A, Westermann F, Ulrich SM, von Deimling A, Fischer M, Witt O (2009) Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res 15(1):91–99CrossRefGoogle Scholar
  25. 25.
    Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42CrossRefGoogle Scholar
  26. 26.
    Peng L, Seto E (2011) Deacetylation of nonhistone proteins by HDACs and the implications in cancer. Handb Exp Pharmacol 206:39–56CrossRefGoogle Scholar
  27. 27.
    Marks P, Rifkind RA, Richon VM et al (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1:194–202CrossRefGoogle Scholar
  28. 28.
    Dokmanovic M, Marks PA (2005) Prospects: histone deacetylase inhibitors. J Cell Biochem 96:293–304CrossRefGoogle Scholar
  29. 29.
    Takumi S, Katsuhiro U, Takeshi O et al (2006) Aberrant expression of histone deacetylase 6 in oral squamous cell carcinoma. Int J Oncol 29:117–124Google Scholar
  30. 30.
    Weidle UH, Grossmann A (2000) Inhibition of histone deacetylases: a new strategy to target epigenetic modifications for anticancer treatment. Anticancer Res 20:1471–1485PubMedGoogle Scholar
  31. 31.
    Rothgiesser KM, Fey M, Hottiger MO (2010) Acetylation of p65 at lysine 314 is important for late NF-κB-dependent gene expression. BMC Genomics 11:22CrossRefGoogle Scholar
  32. 32.
    Buerki C, Rothgiesser KM, Valovka T, Owen HR, Rehrauer H, Fey M, Lane WS, Hottiger MO (2008) Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65. Nucleic Acids Res 36(5):1665–1680CrossRefGoogle Scholar
  33. 33.
    Sterner DE, Berger SL (2000) Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 64:435–459CrossRefGoogle Scholar
  34. 34.
    Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO (2010) SIRT2 regulates NF-κB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci 123:4251–4258CrossRefGoogle Scholar
  35. 35.
    Lehrmann H, Pritchard LL, Harel-Bellan A (2002) Histone acetyltransferases and deacetylases in the control of cell proliferation and differentiation. Adv Cancer Res 86:41–65CrossRefGoogle Scholar
  36. 36.
    Gregoretti IV, Lee YM, Goodson HV (2004) Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol 338(1):17–31CrossRefGoogle Scholar
  37. 37.
    Khan O, La Thangue NB (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol 90:85–94CrossRefGoogle Scholar
  38. 38.
    Kim HJ, Bae SC (2011) Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anticancer drugs. Am J Transl Res 3(2):166–179PubMedGoogle Scholar
  39. 39.
    Johnstone RW, Licht JD (2003) Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4(1):13–18CrossRefGoogle Scholar
  40. 40.
    West AC, Johnstone RW (2014) New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 124:30–39CrossRefGoogle Scholar
  41. 41.
    Blumenschein GR, Kies MS, Papadimitrakopoulou VA et al Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinao, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Investig New Drugs 26(1):81–87Google Scholar
  42. 42.
    Gillenwater AM, Zhong M, Lotan R (2007) Histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis through both mitochondrial and Fas (Cd95) signaling in head and neck squamous carcinoma cells. Mol Cancer Ther 6(11):2967–2975CrossRefGoogle Scholar
  43. 43.
    Takada Y, Gillenwater A, Ichikawa H, Aggarwal BB (2006) Suberoylanilide hydroxamic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing nuclear factor-{kappa}B activation. J Biol Chem 281:5612–5622CrossRefGoogle Scholar
  44. 44.
    Bali P, Pranpat M, Swaby R, Fiskus W, Yamaguchi H, Balasis M, Rocha K, Wang HG, Richon V, Bhalla K (2005) Activity of suberoylanilide hydroxamic acid against human breast cancer cells with amplification of her-2. Clin Cancer Res 11(17):6382–6389CrossRefGoogle Scholar
  45. 45.
    Kelly WK, O’Connor OA, Krug LM et al (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923–3931CrossRefGoogle Scholar
  46. 46.
    Kumar B, Yadav A, Lang JC et al (2015) Suberoylanilide hydroxamic acid (SAHA) reverses chemoresistance in head and neck cancer cells by targeting cancer stem cells via the downregulation of nanog. Genes and Cancer 6(3):169–168PubMedGoogle Scholar
  47. 47.
    Tsai LL, Yu CC, Chang YC et al (2014) Markedly increased Oct4 and Nanog expression correlates with cisplatin resistance in oral squamous cell carcinoma. J Oral Pathol Med 40:621628Google Scholar
  48. 48.
    Lu X, Mazur SJ, Lin T, Appella E, Xu Y (2014) The pluripotency factor nanog promotes breast cancer tumorigenesis and metastasis. Oncogene 33:2655–2664CrossRefGoogle Scholar
  49. 49.
    Chung YL, Wang AJ, Yao LF (2004) Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: implications for increasing therapeutic gain in cancer radiotherapy. Mol Cancer Ther 3:317–325CrossRefGoogle Scholar
  50. 50.
    Christiansen AJ, West A, Banks KM, Haynes NM, Teng MW, Smyth MJ, Johnstone RW (2011) Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies. Proc Natl Acad Sci U S A 108:4141–4146CrossRefGoogle Scholar
  51. 51.
    Manning J, Indrova M, Lubyova B, Pribylova H, Bieblova J, Hejnar J, Simova J, Jandlova T, Bubenik J, Reinis M (2008) Induction of MHC class I molecule cell surface expression and epigenetic activation of antigen-processing machinery components in a murine model for human papilloma virus 16-associated tumors. Immunology 123:218–227PubMedPubMedCentralGoogle Scholar
  52. 52.
    Bourhis J, LeMaitre A, Baujat B et al (2007) Individual patients' data meta-analyses in head and neck cancer. Curr Opin Oncol 19:188–194CrossRefGoogle Scholar
  53. 53.
    Murphy BA, Gilbert J, Cmelak A, Ridner SH (2007) Symptom control issues and supportive care of patients with head and neck cancers. Clin Adv Hematol Oncol 5(10):807–822PubMedGoogle Scholar
  54. 54.
    Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, Komaroff E, Nalysnyk L, Zilberberg MD (2003) Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 66:253–262CrossRefGoogle Scholar
  55. 55.
    Maesschalck T, Dulguerov N, Caparrotti F et al (2016) Comparison of the incidence of osteoradionecrosis with conventional radiotherapy and intensity-modulated radiotherapy. Head Neck 38:1695–1702CrossRefGoogle Scholar
  56. 56.
    Bishop S, Reed WM (2015) The provision of enteral nutritional support during definitive chemoradiotherapy in head and neck cancer patients. J Med Radiat Sci 62:267–276CrossRefGoogle Scholar
  57. 57.
    Hutcheson KA, Lewin JS, Barringer DA, Lisec A, Gunn GB, Moore MWS, Holsinger FC (2012) Late dysphagia after radiotherapy-based treatment of head and neck cancer. Cancer 118:5793–5799CrossRefGoogle Scholar
  58. 58.
    Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, Bonner JA, Harris J, el-Naggar AK, Gillison ML, Jordan RC, Konski AA, Thorstad WL, Trotti A, Beitler JJ, Garden AS, Spanos WJ, Yom SS, Axelrod RS (2014) Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32:2940–2950CrossRefGoogle Scholar
  59. 59.
    Ramalingam SS, Parise RA, Ramanathan RK et al (2007) Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 13:3605–3610CrossRefGoogle Scholar
  60. 60.
    Haigentz M Jr, Kim M, Sarta C, Lin J, Keresztes RS, Culliney B, Gaba AG, Smith RV, Shapiro GI, Chirieac LR, Mariadason JM, Belbin TJ, Greally JM, Wright JJ, Haddad RI (2012) Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer. Oral Oncol 48:1281–1288CrossRefGoogle Scholar
  61. 61.
    Caponigro F, Di Gennaro E, Ionna F et al (2016) Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of head and neck-V-CHANCE trial. BMC Cancer 16(1):918CrossRefGoogle Scholar
  62. 62.
    Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63:7291–7300PubMedGoogle Scholar
  63. 63.
    Workman JL, Kingston RE (1998) Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu Rev Biochem 67:545–579CrossRefGoogle Scholar
  64. 64.
    Sato T, Suzuki M, Sato Y, Echigo S, Rikiishi H (2006) Sequence-dependent interaction between cisplatin and histone deacetylase inhibitors in human oral squamous cell carcinoma cells. Int J Oncol 28:1233–1241PubMedGoogle Scholar
  65. 65.
    Gressette M, Vérillaud B, Jimenez-Pailhès AS, Lelièvre H, Lo KW, Ferrand FR, Gattolliat CH, Jacquet-Bescond A, Kraus-Berthier L, Depil S, Busson P (2014) Treatment of nasopharyngeal carcinoma cells with the histone-deacetylase inhibitor abexinostat: cooperative effects with cis-platin and radiotherapy on patient-derived xenografts. PLoS One 9(3):e91325CrossRefGoogle Scholar
  66. 66.
    Jung M, Kozikowski A, Dritschilo A (2005) Rational design and development of radiation-sensitizing histone deacetylase inhibitors. Chem Biodivers 2:1452–1461CrossRefGoogle Scholar
  67. 67.
    Chinnaiyan P, Vallabhaneni G, Armstrong E, Huang SM, Harari PM (2005) Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 62(1):223–229CrossRefGoogle Scholar
  68. 68.
    Chen X, Wong P, Radany EH, Stark JM, Laulier C, Wong JYC (2012) Suberoylanilide hydroxamic acid as a radiosensitizer through modulation of RAD51 protein and inhibition of homology-directed repair in multiple myeloma. Mol Cancer Res 10(8):1052–1064CrossRefGoogle Scholar
  69. 69.
    Blattmann C, Oertel S, Ehemann V, Thiemann M, Huber PE, Bischof M, Witt O, Deubzer HE, Kulozik AE, Debus J, Weber KJ (2010) Enhancement of radiation response in osteosarcoma and rhabdomyosarcoma cell lines by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 78(1):237–245CrossRefGoogle Scholar
  70. 70.
    Chen X, Wong P, Radany E, Wong JYC (2009) HDAC inhibitor, valproic acid, induces p53–dependent radiosensitization of colon cancer cells. Cancer Biother Radiopharm 24(6):689–699CrossRefGoogle Scholar
  71. 71.
    Losson H, Schnekenburger M, Dicato M, et al (2016) Natural compound histone deacetylase inhibitors (HDACi): synergy with inflammatory signaling pathway modulators and clinical applications in cancer. Molecules 21(11)Google Scholar
  72. 72.
    Wang D, Zhao M, Chen G, Cheng X, Han X, Lin S, Zhang X, Yu X (2013) The histone deacetylase inhibitor vorinostat prevents TNFα-induced necroptosis by regulating multiple signaling pathways. Apoptosis 18(11):1348–1362CrossRefGoogle Scholar
  73. 73.
    Cantley MD, Fairlie DP, Bartold PM, Rainsford KD, le GT, Lucke AJ, Holding CA, Haynes DR (2011) Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro. J Cell Physiol 226(12):3233–3324CrossRefGoogle Scholar
  74. 74.
    Bruzzese F, Leone A, Rocco M, Carbone C, Piro G, Caraglia M, di Gennaro E, Budillon A (2011) HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT. J Cell Physiol 226(9):2378–2390CrossRefGoogle Scholar
  75. 75.
    Kral AM, Ozerova N, Close J, Jung J, Chenard M, Fleming J, Haines BB, Harrington P, Maclean J, Miller TA, Secrist P, Wang H, Heidebrecht RW Jr (2014) Divergent kinetics differentiate the mechanism of action of two HDAC inhibitors. Biochemistry 53(4):725–734CrossRefGoogle Scholar
  76. 76.
    Rinkel RN, Verdonck-de Leeuw IM, Doornaert P, Buter J, de Bree R, Langendijk JA, Aaronson NK, Leemans CR (2016) Prevalence of swallowing and speech problems in daily life after chemoradiation for head and neck cancer based on cut-off scores of the patient-reported outcome measures SWAL-QOL and SHI. Eur Arch Otorhinolaryngol 273(7):1849–1855CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Theodoros N. Teknos
    • 1
    • 2
    Email author
  • J. Grecula
    • 3
  • A. Agrawal
    • 1
  • M. O. Old
    • 1
  • E. Ozer
    • 1
  • R. Carrau
    • 1
  • S. Kang
    • 1
  • J. Rocco
    • 1
  • D. Blakaj
    • 3
  • V. Diavolitsis
    • 3
  • B. Kumar
    • 1
  • P. Kumar
    • 1
  • Q. Pan
    • 1
  • M. Palettas
    • 4
  • L. Wei
    • 4
  • R. Baiocchi
    • 5
  • P. Savvides
    • 5
  1. 1.OtolaryngologyThe Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James)ColumbusUSA
  2. 2.Seidman Cancer CenterUniversity Hospitals Cleveland Medical CenterClevelandUSA
  3. 3.Radiation OncologyThe Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James)ColumbusUSA
  4. 4.Center for BiostatisticsThe Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James)ColumbusUSA
  5. 5.Hematology-Medical OncologyThe Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James)ColumbusUSA

Personalised recommendations