• 3/2/2007
  • Rancho Mirage, CA
  • Jennifer R. Grandis, MD
  • Medscape Today (www.medscape.com)

Introduction:
The Multidisciplinary Head and Neck Cancer Symposium, cosponsored by the American Society for Therapeutic Radiology and Oncology and the American Society of Clinical Oncology, was held in Rancho Mirage, California, from January 18-20, 2007. Several presentations focused on advances in the medical management of patients with head and neck cancer (HNC). Despite increasing awareness of the cancer-inducing effects of tobacco, the incidence of HNC has not decreased worldwide. Efforts to prevent these tumors through pharmacologic intervention have largely failed, and early detection strategies have not been successful. Thus, most patients with HNC present with advanced (stages III and IV) disease. Oral cavity tumors are treated primarily with surgical resection due to the toxicity of radiation in this region (eg, osteoradionecrosis). Advanced tumors of the pharynx and larynx are generally treated with combined modality therapy (chemoradiation [CRT]), with surgery reserved for neck dissection when the patient presents with advanced neck disease (N2 or N3) and/or has an incomplete response in the neck to CRT. The major advance in the management of HNC continues to be the integration of targeted therapeutics into treatment regimens.

Inhibiting the Epidermal Growth Factor Receptor:
The landmark Radiation Therapy Oncology Group trial[1] comparing the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab plus radiation vs radiation alone led to approval of this agent by the US Food and Drug Administration (FDA) in 2006 for the treatment of HNC. Cetuximab was the first drug approved for HNC in more than 40 years. Support for EGFR-targeted therapies was based on the observation that head and neck tumors express EGFR at high levels compared with levels in normal mucosa, and that EGFR expression correlates with decreased survival.[2,3] Preclinical studies demonstrated the antitumor effects of targeting EGFR in HNC models.[4]

Several presenters discussed evolving data on the clinical use of cetuximab in patients with HNC. Suntharalingam and colleagues[5] at the University of Maryland presented the preliminary findings of a phase 2 trial of weekly cetuximab in combination with paclitaxel and daily radiation in patients with locally advanced HNC. Patients received cetuximab as a loading dose of 400 mg/m2 followed by weekly doses of 250 mg/m2. Chemotherapy consisted of paclitaxel (40 mg/m2) and carboplatin (AUC 2). Radiotherapy was delivered at 1.8 Gy/day to a total dose of 70.2 Gy to gross disease. Eighteen patients were available for analysis of toxicity and response. No grade 4 toxicities were observed; 89% of patients developed grade 3 mucositis and 11% had grade 3 field skin desquamation. A large proportion (72%) achieved a complete response 2 months after completion of therapy. These results suggest that the combination of cetuximab with CRT is safe and effective in HNC. With several large studies nearing or having reached completion, the role of primary treatment with cetuximab/CRT should be defined in the near future.

Panitumumab is a fully humanized anti-EGFR monoclonal antibody that is also being studied in HNC. Preclinical data suggest that it is active alone as well as in combination with radiation.[6] Clinical studies are underway.

In addition to monoclonal antibodies, tyrosine kinase inhibitors (TKIs) have been developed to target EGFR. The EGFR inhibitor erlotinib is approved for the treatment of non-small-cell lung cancer and pancreatic cancer, but its use in HNC remains undetermined. Preclinical data presented by Wheeler and colleagues[7] from the University of Wisconsin suggested that cancer cells that are resistant to cetuximab are sensitive to EGFR TKIs, providing a rationale for combined EGFR inhibition with an antibody plus a TKI. The same group assessed the effects of targeting ErbB2 using a monoclonal antibody (2C4) and found that this strategy could also overcome intrinsic resistance to cetuximab.[8]

Other Targets
Tumor initiation and progression require the development of tumor vasculature. A number of strategies have been developed to target the angiogenic process. Angiogenesis is a plausible target in HNC, and several agents, including small molecules and antibodies, are under active clinical investigation.

Elser and colleagues[9] from Toronto’s Princess Margaret Hospital discussed the effects of sorafenib, an oral multikinase inhibitor that targets Raf kinase and vascular endothelial growth factor receptor (VEGFR)-2 as well as other kinases. They conducted a phase 2 trial in patients with recurrent or metastatic HNC using a dose of 400 mg twice a day. Preliminary analysis of paired biopsies from a subset of patients demonstrated that sorafenib decreased angiogenesis in selected signaling pathways. These findings demonstrate the utility of performing biomarker assays in tissues from patients treated with these novel agents.

Bevacizumab is an anti-VEGF monoclonal antibody that is FDA-approved for use in other malignancies. Savvides and colleagues[10] from Case Comprehensive Cancer Center in Cleveland reported the preliminary results of a phase 2 study examining the efficacy of bevacizumab in combination with docetaxel and radiation in locally advanced HNC. Eight patients with stage IV disease completed therapy and 5 of 8 had a posttreatment neck dissection that demonstrated a pathologic complete response. These patients are now receiving adjuvant bevacizumab. The addition of this agent to curative CRT appears to be feasible. No episodes of severe bleeding were noted, which has been a concern with this agent. Khuntia and colleagues[11] from the University of Wisconsin presented the design of an ongoing phase 1 trial of neoadjuvant bevacizumab followed by concurrent radiation, cisplatin, and bevacizumab for locally advanced HNC. Results of this study were not yet available.

Src family kinases have emerged as potential targets in cancer therapy. Src is directly phosphorylated by the EGFR at tyrosine residue 845, a phosphorylation that has been shown to be important in breast cancer.[12] EGFR phosphorylation is required for Src activation in HNC.[13] In addition, Src serves a central function in the activation of EGFR by G-protein-coupled receptors.[14] Src targeting using small molecule inhibitors has demonstrated antitumor effects in preclinical HNC models.[15] Raju and colleagues[16] from MD Anderson Cancer Center presented additional preclinical evidence demonstrating that dasatinib, an inhibitor of c-Src, enhances the radiosensitivity of HNC cell lines.

The receptor tyrosine kinase c-MET is frequently overexpressed in cancer cells including HNC where levels are associated with decreased survival.[17] Siewart and colleagues[18] from the University of Chicago presented evidence in preclinical HNC models that targeting c-MET may be efficacious. Phase 1 trials with c-MET inhibitors are planned.

Natural products are also being explored as potential therapeutic reagents in HNC. Curcumin, commonly known as the spice turmeric that is derived from the East Indian plant Curcuma longa, has been shown to have anticancer properties in several malignancies.[19] Wang and colleagues[20] from UCLA reported growth inhibitory effects with the use of curcumin in HNC preclinical models. Clinical trials investigating the cancer chemopreventive effects of natural products including curcumin are underway.

Conclusion
In summary, information presented at this meeting focused on the potential value of adding molecular targeted therapies to standard chemoradiation strategies for the treatment of head and neck cancer. Approaches that target the EGFR are among the most developed. Other receptor and nonreceptor kinase targeting strategies are under active clinical investigation. The precise targeting strategy that may prove beneficial for an individual patient likely depends on the specific genetic and epigenetic alterations in the individual’s tumor. Additional investigations that focus on characterizing the effects of these agents in HNC tumors are warranted to facilitate clinical development. Moreover, the increasing number of molecular targeting strategies in clinical development underscores the need to identify which HNC patients will respond to specific therapies. Studies that characterize the tumor response to targeted therapies are needed to begin to realize the promise of personalized medicine.

References:
(1) 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;354:567-578.

(2) Rubin Grandis J, Melhem MF, Gooding WE, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90:824-832. Abstract

(3) Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients. Abstract

(4) Rubin Grandis J, Chakraborty A, Melhem MF, Zeng Q, Tweardy DJ. Inhibition of epidermal growth factor receptor gene expression and function decreases proliferation of head and neck squamous carcinoma but not normal mucosal epithelial cells. Oncogene. 1997;15:409-416. Abstract

(5) Suntharalingam M, Taylor R, Wolf J, Cullen K, Zimrin A. Initial report of phase II trial of weekly cetuximab, CBDCA, paclitaxel and daily RT in patients with locally advanced SCCHN. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 95

(6) Cannon MJ, Armstrong E, Huang S, et al. Panitumumab, a fully anti-EGFR monoclonal antibody, augments radiation response in xenograft models of squamous cell carcinoma of the head and neck. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 174

(7) Wheeler DL, Kruser TJ, Huang S, Armstrong E, Harari PM. Acquired resistance to cetuximab; rationale for sequential therapies directed against the EGFR. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 96

(8) Kruser TJ, Wheeler DL, Huang S, et al. Dual agent targeting of EGFR and ErbB2 with cetuximab and 2C4: a strategy to overcome acquired resistance. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 122.

(9) Elser C, Siu LL, Agulnik M, et al. Study of the biologic effects of sorafenib (Nexavar, Bay 43-9006) on tumor survival pathways and angiogenesis in patients with recurrent and/or metastatic head and neck cancer. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 116.

(10) Savvides P, Greskovich J, Bokar J, et al. Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck (SCCHN). Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 122.

(11) Khuntia D, Jeraj R, Kruser TJ, et al. Phase I trial of neoadjuvant bevacizumab followed by concurrent radiation, cisplatin and bevacizumab for locoregionally advanced squamous cell carcinoma of the head and neck. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 63.

(12) Riggins RB, Thomas KS, Ta HQ, et al. Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Cancer Res. 2006;66:7007-7015. Abstract

(13) Xi S, Zhang Q, Dyer KF, et al. Src kinases mediate STAT growth pathways in squamous cell carcinoma of the head and neck. J Biol Chem. 2003;278:31574-31583. Abstract

(14) Zhang Q, Thomas SM, Xi S, et al. SRC family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck cancer cells. Cancer Res. 2004;64:6166-6173. Abstract

(15) Johnson FM, Saigal B, Talpaz M, Donato NJ. Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res. 2005;11:6924-6932. Abstract

(16) Raju U, Koto M, Johnson F, Glisson B, Milas L, Ang KK. Dasatinib (SPRYCEL(r), formerly BMS-354825), an inhibitor of c-SRC, enhances the radiosensitivity of head and neck cancer cell lines. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 197. Abstract 197

(17) Lo Muzio L, Furina A, Rubini C, et al. Effect of c-Met expression on survival in head and neck squamous cell carcinoma. Tumour Biol. 2006;27:115-121. Abstract

(18) Seiwert T, Janamanchi V, Klein-Szanto A, et al. The receptor tyrosine kinase c-MET as a novel therapeutic target in head and neck cancer. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 93.

(19) Aggarwal BB, Banerjee S, Bharadwaj U, Sung B, Shishodia S, Sethi G. Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines. 2006 Dec 15; [Epub ahead of print].

(20) Wang D, Tang C, Ho B, Srivatsan E, Wang M. Liposomal curcumin suppresses growth of head and neck squamous cell carcinoma. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 121.