Opinion statement
Worldwide more than a half million people develop Head and Neck cancer annually. Despite a significant decrease in smoking, about 40,000 new patients are diagnosed with carcinoma of the head and neck annually in the United States, and 11,000 of them succumb to their disease. More than 90% of these cancers are squamous cell carcinoma. The survival rates of patients with squamous cell carcinoma of the head and neck (SCCHN) have not improved significantly despite multimodality therapy including surgery, radiation therapy, and chemotherapy. Recently, molecular targeted agents have shown significant improvement in clinical outcomes in chronic myelogeneous leukemia with imatinib, breast cancer with trastuzumab, colon cancer with bevacizumab and cetuximab, and renal cell cancer with sorafenib and sunitinib. In SCCHN the epidermal growth factor receptor (EGFR) antibody cetuximab has shown promising results in a phase III trial in combination with radiation. How best to integrate these agents with the traditional treatment modalities of surgery, radiotherapy, and cytotoxic chemotherapy is of vital importance but has yet to be determined. This article will discuss the biology of molecular targeted agents as well as current clinical trials and future directions of these agents in SCCHN.
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Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100(1):57–70
Adjei AA, Hidalgo M: Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol 2005, 23(23):5386–5403
The basis of signal transduction in cancer therapy is well described.
Marshall J: Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. Cancer 2006, 107(6):1207–1218
The future prospects of EGFR inhibitors are introduced in this paper.
Burtness B: The role of cetuximab in the treatment of squamous cell cancer of the head and neck. Expert Opin Biol Ther 2005, 5(8):1085–1093
Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH: Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1983, 1(5):511–529
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006, 354(6):567–578
This landmark study reports cetuximab’s advantage with RT over RT alone in SCCHN.
Pfister DG, Su YB, Kraus DH, Wolden SL, Lis E, Aliff TB, Zahalsky AJ, Lake S, Needle MN, Shaha AR 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(7):1072–1078
Buentzel J, Vries Ad, Micke O: Experience with cetuximab plus paclitaxel/carboplatinum in primary platinum-resistant recurrent head and neck cancer [abstract 6077] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6077
Kies MS, Garden AS, Holsinger C, Papadimitrakopoulou V, El-Naggar AK, Gillaspy K, Lewin J, Lu C, Villalobos S, Glisson BS: Induction chemotherapy (CT) with weekly paclitaxel, carboplatin, and cetuximab for squamous cell carcinoma of the head and neck (HN) [abstract 5520] J Clin Oncol, ASCO Ann Meet Proc 2006, 24(18S, Part I, June 20 Supplement):5520
Wanebo HJ, Ghebremichael M, Burtness B, Spencer S, Ridge J, Forastiere A, Ghebremichael M: Phase II evaluation of cetuximab (C225) combined with induction paclitaxel and carboplatin followed by C225, paclitaxel, carboplatin, and radiation for stage III/IV operable squamous cancer of the head and neck (ECOG, E2303) [abstract 6015] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6015
Argiris A, Karamouzis MV, Heron DE, Smith R, Ferris R, Lai S, Kim S, Branstetter B, Johnson J, Grandis J: Phase II trial of docetaxel (T), cisplatin (P), and cetuximab (E) followed by concurrent radiation (RT), P, and E in locally advanced head and neck squamous cell carcinoma (HNSCC) [abstract 6051] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6051
Merlano C, Russi EG, Benasso M, Colantonio I, Vigna Taglianti R, Lanzilotta L, Vigo V, Bacigalupo A: Cetuximab (C-mab) and chemo-radiation (CT-RT) for loco-regional advanced squamous cell carcinoma of the head and neck (HNC): A phase II study [abstract 6043] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6043
Vermorken J, Mesia R, Vega V, Remenar E, Hitt R, Kawecki A, Rottey S, Amellal N, Cupissol D, Licitra L: Cetuximab extends survival of patients with recurrent or metastatic SCCHN when added to first line platinum based therapy - Results of a randomized phase III (Extreme) study. ASCO Ann Meet 2007
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(34):8646–8654
Hitt R, Irigoyen A, Nuñez J, Grau J, Saenz JG, Pastor M, Jara C, Giron CG, Hidalgo M, Hernandez JC: Phase II study of combination cetuximab and weekly paclitaxel in patients with metastatic/recurrent squamous cell carcinoma of head and neck (SCCHN): Spanish Head and Neck Cancer Group (TTCC) [abstract 6012] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6012
A Phase I Study of Adjuvant OSI-774 (Tarceva®) in Patients Following Combined Chemo-Radiotherapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (NCT00079053). National Cancer Institute of Canada
A Randomised, Double-Blind, Placebo-Controlled, Multi-Centre, Phase III Study of Post-Operative Adjuvant Lapatinib or Placebo and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib or Placebo Monotherapy in High-Risk Subjects With Resected Squamous Cell Carcinoma of the Head and Neck (NCT00424255). International
Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, Fu KK, Milas L: Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002, 62(24):7350–7356
Kies M, Ghebremichael M, Katz T: EGFR expression by immunohistochemistry (IHC) and response to chemotheraphy and cetuximab in squamous cell carcinoma of the head and neck (SCCHN) [abstract 6024]. J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6024
Saltz L, Kies M, Abbruzzese JL, Azarnia N, Needle M: The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Abstract 817. Proc Am Soc Clin Oncol 2003, 22
Perez-Soler R, Saltz L: Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 2005, 23(22):5235–5246
This article well describes the rash seen with cetuximab.
Cutsem EV, Humblet Y, Gelderblom H, Vermorken JB, Viret F, Glimelius B, Ciardiello F, Gallerani E, Amellal N, Peeters M: Cetuximab dose-escalation study in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic and efficacy data of a randomized study. Abstract 237. Gastrointestinal Cancers Symposium, 2007
Lenz HJ: Anti-EGFR mechanism of action: antitumor effect and underlying cause of adverse events. Oncology (Williston Park) 2006, 20(5 Suppl 2):5–13
This article describes EGFR pathway blockade effects and side effects.
Huang S, Armstrong EA, Benavente S, Chinnaiyan P, Harari PM: Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res 2004, 64(15):5355–5362
Fischel JL, Formento P, Milano G: Epidermal growth factor receptor double targeting by a tyrosine kinase inhibitor (Iressa) and a monoclonal antibody (Cetuximab). Impact on cell growth and molecular factors. Br J Cancer 2005, 92(6):1063–1068
Randomized Study of Bevacizumab/Tarceva and Tarceva/Sulindac in Squamous Cell Carcinoma of the Head and Neck (NCT00392665). Dana-Farber Cancer Institute
Concurrent Angiogenic and EGFR Blockade in Conjunction With Curative Intent Chemoradiation for Locally Advanced Head and Neck Cancer (NCT00140556). Duke University
A Phase II Trial of Cetuximab and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer (NCT00409565). University of Pittsburgh
Cohen EE, Rosen F, Stadler WM, Recant W, Stenson K, Huo D, Vokes EE: Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003, 21(10):1980–1987
Cohen EE, Kane MA, List MA, Brockstein BE, Mehrotra B, Huo D, Mauer AM, Pierce C, Dekker A, Vokes EE: Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2005, 11(23):8418–8424
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(1):77–85
Cohen EE, Haraf DJ, Stenson KM, Blair E, Brockstein BE, Mauer AM, Dekker A, Williams R, Lester E, Vokes EE: Integration of Gefitinib (G), into a Concurrent Chemoradiation (CRT) Regimen Followed by G Adjuvant Therapy in Patients with Locally Advanced Head and Neck Cancer (HNC)—a Phase II Trial [abstract 5506] J Clin Oncol, ASCO Ann Meet Proc 2005, 23(16S, Part I of II, June 20 Supplement):5506
Herchenhorn D, Dias FL, Pineda RM, Fonseca AJ, Bezerra M, Ferreira CG, Knust RE, Fontão K, Martins RG: Phase II study of erlotinib combined with cisplatin and radiotherapy for locally advanced squamous cell carcinoma of the head and neck [abstract 6033] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6033
Kim ES, Kies MS, Glisson BS, Tsao A, Ginsberg LE, Holsinger FC, Burke BJ, Truong M, Papadimitrakopoulou VA, Lippman SM: Final results of a phase II study of erlotinib, docetaxel and cisplatin in patients with recurrent/metastatic head and neck cancer [abstract 6013] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6013
Glisson BS, Saigal B, Xu Y, Johnson FM: Sequence-dependent cytoxicity of docetaxel and erlotinib in head and neck squamous cell carcinoma (HNSCC) [abstract 6084] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6084
An Open-Labeled Trial With a Dose-Escalation Part and a Parallel Group Design Investigating Zalutumumab, an Anti-EGF Receptor Antibody, in Combination With Chemo-Radiation as First Line Treatment of Patients With Cancer of the Head and Neck (NCT00401401). Internation
An Open-Labeled Randomized Parallel Group Trial of Zalutumumab, a Human Monoclonal Anti-EGFr Antibody, in Combination With Best Supportive Care (BSC) vs BSC, in Pts With Non-Curable SCCHN Who Have Failed Standard Platinum-Based Chemotherapy (NCT00382031). International
Ferrara N: Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 2004, 9(Suppl 1):2–10
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L: VEGF receptor signaling—in control of vascular function. Nat Rev Mol Cell Biol 2006, 7(5):359–371
This article reviews the VEGF pathway in detail.
Mineta H, Miura K, Ogino T, Takebayashi S, Misawa K, Ueda Y, Suzuki I, Dictor M, Borg A, Wennerberg J: Prognostic value of vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinomas. Br J Cancer 2000, 83(6):775–781
Choong NW, Haraf DJ, Cohen EE, Stenson KM, Blair EA, Dekker A, Williams R, Karrison TG, Vokes EE: Randomized phase II study of concomitant chemoradiotherapy with 5-fluorouracil-hydroxyurea (FHX) compared to FHX and bevazicumab (BFHX) in intermediate stage head and neck cancer (HNC) [abstract 6034] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6034
Karamouzis MV, Friedland D, Johnson R, Rajasenan K, Branstetter B, Argiris A: Phase II trial of pemetrexed (P) and bevacizumab (B) in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC): An interim analysis [abstract 6049] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6049
Savvides P, Greskovich J, Bokar J, Stepnick DW, P. Fu FJ, Patel C, Wasman J, Remick S, Lavertu P: Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck (SCCHN) [abstract 6068] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6068
Williamson SK, Moon J, Huang CH, Guaglianone P, Wolf GT, Urba SG: A phase II trial of sorafenib in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC): A Southwest Oncology Group (SWOG) trial [abstract 6044] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6044
Abidoye OO, Cohen EE, Wong SJ, Kozloff MF, Nattam SR, Stenson KM, Blair EA, Day S, Dancey JE, Vokes EE: A phase II study of lapatinib (GW572016) in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) [abstract 5568] J Clin Oncol, ASCO Ann Meet Proc 2006, 25(18S, Part I, June 20 Supplement):5568
Harrington KJ, Bourhis J, Nutting CM, Rosine D, Theodosiou AM, Gardiner S, Berger MS, Beelen AP, Stead AG, El-Hariry IA: A phase I, open-label study of lapatinib plus chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck [abstract 5553] J Clin Oncol, ASCO Ann Meet Proc 2006, 24(18S, Part I, June 20 Supplement):5553
An Open Label, Multi-Center, Phase I Study To Assess The Maximum Tolerated Dose of ZD6474 (ZACTIMA) Given Concomitantly With Radiation Therapy or Concomitantly With Weekly Cisplatin Chemotherapy and Radiation Therapy in Patients With Previously Untreated, Unresected, Stage III-IV Head and Neck Squamous Cell Carcinoma (NCT00411710). M. D. Anderson Cancer Center
Boccadoro M, Morgan G, Cavenagh J: Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy. Cancer Cell Int 2005, 5(1):18
Phase II Two Arm Trial of the Proteasome Inhibitor, PS-341 (Velcade) in Combination With Irinotecan or PS-341 Alone Followed by the Addition of Irinotecan at Time Progression in Patients With Locally Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (NCT00103259). Eastern Cooperative Oncology Group (ECOG)
A Phase I Study of Concomitant Therapy With Proteasome Inhibitor PS-341 and Radiation in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (NCT00016003). National Cancer Institute (NCI)
Amornphimoltham P, Patel V, Sodhi A, Nikitakis NG, Sauk JJ, Sausville EA, Molinolo AA, Gutkind JS: Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res 2005, 65(21):9953–9961
A Phase I Study of Weekly Low-Dose Cisplatin Plus Escalating Doses of Oral RAD001(Everolimus) for Patients With Advanced Solid Tumors (NCT00423865). Memorial Sloan-Kettering Cancer Center
Yin X, Zhang H, Burrows F, Zhang L, Shores CG: Potent activity of a novel dimeric heat shock protein 90 inhibitor against head and neck squamous cell carcinoma in vitro and in vivo. Clin Cancer Res 2005, 11(10):3889–3896
Quenneville J, Fitsialos D, Rasamoelisolo M, Cross M, Glover N, MacDonald G: A phase I open-label study to evaluate safety, tolerability and pharmacokinetic (PK) profile of VB4-845, an anti-EpCAM immunotoxin, in subjects with SCCHN [abstract 5539] J Clin Oncol, ASCO Ann Meet Proc 2005, 23(16S, Part I of II, June 1 Supplement):5539
Bolden JE, Peart MJ, Johnstone RW: Anticancer activities of histone deacetylase inhibitors. Nat Rev 2006, 5(9):769–784
Slomiany MG, Black LA, Kibbey MM, Tingler MA, Day TA, Rosenzweig SA: Insulin-like growth factor-1 receptor and ligand targeting in head and neck squamous cell carcinoma. Cancer Lett 2007, 248(2):269–279
D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, Westra WH, Gillison ML: Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007, 356(19):1944–1956
Fakhry C, Westra W, Li S, Cmelak A, Ridge J, Pinto H, Forastiere A, Gillison M: Prognostic significance of human papillomavirus (HPV) tumor status for patients with head and neck squamous cell carcinoma (HNSCC) in a prospective, multi-center phase II clinical trial [abstract 6000] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6000
Chaturvedi A, Engels E, Anderson W, Gillison M: Incidence trends for human papillomavirus-related (HPV-R) and unrelated (HPV-U) head and neck squamous cell carcinomas (HNSCC) in the United States (US) [abstract 6001] J Clin Oncol, ASCO Ann Meet Proc 2007, 25(18S, Part I, June 20 Supplement):6001
MAGE-A3/HPV 16 Peptide Based Immunotherapeutic Vaccines for Squamous Cell Carcinoma of the Head and Neck (NCT00257738). University of Maryland
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Shirai, K., O’Brien, P.E. Molecular Targets in Squamous Cell Carcinoma of the Head and Neck. Curr. Treat. Options in Oncol. 8, 239–251 (2007). https://doi.org/10.1007/s11864-007-0030-4
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DOI: https://doi.org/10.1007/s11864-007-0030-4