Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 4, pp 649–660 | Cite as

A phase II study of sunitinib in patients with recurrent and/or metastatic non-nasopharyngeal head and neck cancer

  • George Fountzilas
  • Anna Fragkoulidi
  • Anna Kalogera-Fountzila
  • Martha Nikolaidou
  • Mattheos Bobos
  • Julien Calderaro
  • Felipe Andreiuolo
  • Marios Marselos
Original Article

Abstract

Purpose

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) bear a grave prognosis. There are unmet needs for the development of novel agents for this incurable disease. Angiogenesis is an important biological process in SCCHN. We, therefore, evaluated the activity and safety of sunitinib, an oral tyrosine kinase inhibitor that targets multiple receptors, in patients with RM-SCCHN.

Patients and methods

Seventeen patients were treated with sunitinib 50 mg per day administrated in 4-week cycles followed by a rest period of 2 weeks. Sunitinib and SU012662 plasma levels were determined based on a validated liquid chromatography-tandem mass spectrometry method and pharmacokinetic data were fitted in a non-compartmental analysis.

Results

Totally, 28 6-week cycles of treatment with sunitinib were administered (median, 2 cycles). Only three patients demonstrated stabilization of the disease; therefore, the study had to be terminated prematurely due to futility. Grade 3 toxicities, apart from fatigue, were infrequent. Other frequently reported side effects were skin discoloration, neutropenia, and thrombocytopenia. Ten various bleeding complications were reported in seven patients. Mean maximum concentrations (C max) were reached during the first day of treatment for sunitinib at 38.98 (±22.66) ng/ml and for SU012662 at 11.12 (±24.57) ng/ml. Our results showed that SU012662 has a longer half-life and a larger volume of distribution than the parent drug sunitinib. None of the biological markers tested was of any prognostic value.

Conclusions

According to our findings, sunitinib monotherapy was not proven active in RM-SCCHN, and no further development of the drug in this indication is warranted.

Keywords

Head and neck cancer Pharmacokinetic analysis Sunitinib Angiogenesis 

Notes

Acknowledgments

The authors wish to thank Ms. A.G. Eleftheraki, MSc., HeCOG Data Office, for statistical analysis, Ms. Th. Spinari, HeCOG Data Office and Ms. M. Malliota, Papageorgiou Hospital for tumor tissue and blood sample collection, Ms. M. Moschoni, HeCOG Data Office for data coordination, and Ms. S. Dallidou for secretarial assistance. The trial was supported by a Hellenic Cooperative Oncology Group Research Grant (HE R_5/06) and by an Independent Investigator Research Grant by Pfizer.

References

  1. 1.
    Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18(3):581–592CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics. CA Cancer J Clin 57(1):43–66CrossRefPubMedGoogle Scholar
  3. 3.
    Colevas AD (2006) Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 24(17):2644–2652 (Review)CrossRefPubMedGoogle Scholar
  4. 4.
    Specenier PM, Vermorken JB (2008) Recurrent head and neck cancer: current treatment and future prospects. Exp Rev Anticancer Ther 8(3):375–391CrossRefGoogle Scholar
  5. 5.
    Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359(11):1116–1127CrossRefPubMedGoogle Scholar
  6. 6.
    Chow LQ, Eckhardt SG (2007) Sunitinib: from rational design to clinical efficacy. J Clin Oncol 25(7):884–896CrossRefPubMedGoogle Scholar
  7. 7.
    Beeram M, Patnaik A, Rowinsky EK (2005) Raf: a strategic target for therapeutic development against cancer. J Clin Oncol 23(27):6771–6790CrossRefPubMedGoogle Scholar
  8. 8.
    Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438(7070):967–974CrossRefPubMedGoogle Scholar
  9. 9.
    Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011–1027CrossRefPubMedGoogle Scholar
  10. 10.
    Kyzas PA, Cunha IW, Ioannidis JP (2005) Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res 11(4):1434–1440CrossRefPubMedGoogle Scholar
  11. 11.
    Ninck S, Reisser C, Dyckhoff G, Helmke B, Bauer H, Herold-Mende C (2003) Expression profiles of angiogenic growth factors in squamous cell carcinomas of the head and neck. Int J Cancer 106(1):34–44CrossRefPubMedGoogle Scholar
  12. 12.
    Kyzas PA, Stefanou D, Batistatou A, Agnantis NJ (2005) Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2. Mod Pathol 18(4):485–494CrossRefPubMedGoogle Scholar
  13. 13.
    Neuchrist C, Erovic BM, Handisurya A, Fischer MB, Steiner GE, Hollemann D, Gedlicka C, Saaristo A, Burian M (2003) Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck. Head Neck 25(6):464–474CrossRefPubMedGoogle Scholar
  14. 14.
    Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24(1):16–24CrossRefPubMedGoogle Scholar
  15. 15.
    Miettinen M, Sobin LH, Lasota J (2005) Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1,765 cases with long-term follow-up. Am J Surg Pathol 29(1):52–68CrossRefPubMedGoogle Scholar
  16. 16.
    Jubb AM, Pham TQ, Hanby AM, Frantz GD, Peale FV, Wu TD, Koeppen HW, Hillan KJ (2004) Expression of vascular endothelial growth factor, hypoxia inducible factor 1 alpha, and carbonic anhydrase IX in human tumours. J Clin Pathol 57(5):504–512CrossRefPubMedGoogle Scholar
  17. 17.
    Gunningham SP, Currie MJ, Han C, Robinson BA, Scott PA, Harris AL, Fox SB (2000) The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. Clin Cancer Res 6(11):4278–4286PubMedGoogle Scholar
  18. 18.
    Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla P, Raymond E (2006) Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24(1):25–35CrossRefPubMedGoogle Scholar
  19. 19.
    Bello CL, Sherman L, Zhou J, Verkh L, Smeraglia J, Mount J, Klamerus KJ (2006) Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs 17(3):353–358CrossRefPubMedGoogle Scholar
  20. 20.
    Choong NW (2008) Phase II trial of sunitinib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol 26 (abstr 6064)Google Scholar
  21. 21.
    Kyzas PA, Stefanou D, Agnantis NJ (2004) Immunohistochemical expression of vascular endothelial growth factor correlates with positive surgical margins and recurrence in T1 and T2 squamous cell carcinoma (SCC) of the lower lip. Oral Oncol 40(9):941–947CrossRefPubMedGoogle Scholar
  22. 22.
    Hitt R, Jimeno A, Rodríguez-Pinilla M, Rodríguez-Peralto JL, Millán JM, López-Martín A, Brandariz A, Peña C, Cortés-Funes H (2004) Phase II trial of cisplatin and capecitabine in patients with squamous cell carcinoma of the head and neck, and correlative study of angiogenic factors. Br J Cancer 91(12):2005–2011CrossRefPubMedGoogle Scholar
  23. 23.
    Ongkeko WM, Altuna X, Weisman RA, Wang-Rodriguez J (2005) Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am J Clin Pathol 124(1):71–76CrossRefPubMedGoogle Scholar
  24. 24.
    Elser C, Siu LL, Winquist E, Agulnik M, Pond GR, Chin SF, Francis P, Cheiken R, Elting J, McNabola A, Wilkie D, Petrenciuc O, Chen EX (2007) 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 25(24):3766–3773CrossRefPubMedGoogle Scholar
  25. 25.
    Miyahara M, Tanuma J, Sugihara K, Semba I (2007) Tumor lymphangiogenesis correlates with lymph node metastasis and clinicopathologic parameters in oral squamous cell carcinoma. Cancer 110(6):1287–1294CrossRefPubMedGoogle Scholar
  26. 26.
    Tanigaki Y, Nagashima Y, Kitamura Y, Matsuda H, Mikami Y, Tsukuda M (2004) The expression of vascular endothelial growth factor-A and -C, and receptors 1 and 3: correlation with lymph node metastasis and prognosis in tongue squamous cell carcinoma. Int J Mol Med 14(3):389–395PubMedGoogle Scholar
  27. 27.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603CrossRefPubMedGoogle Scholar
  28. 28.
    Saltz LB, Rosen LS, Marshall JL, Belt RJ, Hurwitz HI, Eckhardt SG, Bergsland EK, Haller DG, Lockhart AC, Rocha Lima CM, Huang X, DePrimo SE, Chow-Maneval E, Chao RC, Lenz HJ (2007) Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. J Clin Oncol 25(30):4793–4799CrossRefPubMedGoogle Scholar
  29. 29.
    Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, Lehman M, Adams BJ, Bello CL, DePrimo SE, Baum CM, Miller KD (2008) Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 26(11):1810–1816CrossRefPubMedGoogle Scholar
  30. 30.
    Socinski MA, Novello S, Brahmer JR, Rosell R, Sanchez JM, Belani CP, Govindan R, Atkins JN, Gillenwater HH, Pallares C, Tye L, Selaru P, Chao RC, Scagliotti GV (2008) Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol 26(4):650–656CrossRefPubMedGoogle Scholar
  31. 31.
    Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9(1):327–337PubMedGoogle Scholar
  32. 32.
    Silva P, Slevin NJ, Sloan P, Valentine H, Cresswell J, Ryder D, Price P, Homer JJ, West CM (2008) Prognostic significance of tumor hypoxia inducible factor-1alpha expression for outcome after radiotherapy in oropharyngeal cancer. Int J Radiat Oncol Biol Phys 72(5):1551–1559PubMedGoogle Scholar
  33. 33.
    Kappler M, Taubert H, Holzhausen HJ, Reddemann R, Rot S, Becker A, Kuhnt T, Dellas K, Dunst J, Vordermark D, Hänsgen G, Bache M (2008) Immunohistochemical detection of HIF-1alpha and CAIX in advanced head-and-neck cancer prognostic role and correlation with tumor markers and tumor oxygenation parameters. Strahlenther Onkol 184(8):393–399CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • George Fountzilas
    • 1
  • Anna Fragkoulidi
    • 1
  • Anna Kalogera-Fountzila
    • 2
  • Martha Nikolaidou
    • 3
  • Mattheos Bobos
    • 4
  • Julien Calderaro
    • 5
  • Felipe Andreiuolo
    • 5
  • Marios Marselos
    • 3
  1. 1.Department of Medical Oncology, “Papageorgiou” HospitalAristotle University of Thessaloniki School of MedicineThessalonikiGreece
  2. 2.Department of Radiology, AHEPA HospitalAristotle University of Thessaloniki School of MedicineThessalonikiGreece
  3. 3.Department of PharmacologyUniversity of Ioannina School of MedicineIoanninaGreece
  4. 4.Department of PathologyAristotle University of Thessaloniki School of MedicineThessalonikiGreece
  5. 5.Translational Research LaboratoryInstitut de Cancerologie Gustave RoussyVillejuif CedexFrance

Personalised recommendations