Treatment of Locally Advanced Head and Neck Cancer: Historical and Critical Review

Muhyi Al-Sarraf, MD, FRCPC, FACP


Cancer Control. 2002;9(5) 

In This Article

Targeted Therapy

Novel biologic agents have been developed to target multiple specific regions of the cancer cells. Protein tyrosine kinases are major components of cell signaling pathways. The various subfamilies of these kinases include receptors for epidermal growth factor receptors (EGFR), platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor, and hepatocyte growth factor. EGFR is one of four receptors critical to cellular proliferation, differentiation, and survival, and it is widely expressed in malignant tissue, especially in squamous cell carcinoma of the head and neck. EGFR blockers, such as anti-EGFR monoclonal antibodies, tyrosine kinase inhibitors, ligand conjugates, and antisense oligonucleotides, have been investigated in patients with head and neck cancers.

Anti-EGFR antibodies target the extracellular domain. Small molecules, such as the tyrosine kinase inhibitors, target the intracellular tyrosine kinase signaling pathways and thus inhibit the EGFR pathways. EGFR expression was found to correlate with locoregional control and overall survival but not with the incidence of distant failure in patients with head and neck cancers. Table 9 summarizes recent reported results with these agents given alone or with platinum drugs.[43,44,45,46,47,48,49] Most of these patients were previously treated with first-line chemotherapy and even some with second-line chemotherapy for recurrent disease. These agents are not miracle drugs in patients with head and neck cancers. Used alone, response rates are approximately 10%; with single-agent chemotherapy, the response rates are about 20%. Some investigators have tried to inflate the rate of response rate by adding the group of patients with stable disease, and others have tried to correlate the response to the incidence and degrees of skin toxicities. Neither approach is correct or acceptable.

The ECOG study comparing single-dose cisplatin to cisplatin plus C225 (cetuximab) in patients with previously untreated recurrent or metastatic cancers reported an incidence rate of approximately 35% to 40% stable disease in both arms.[47] This randomized trial had design flaws. Neither ECOG nor other groups or centers give single-agent cisplatin as first-line treatment for these patients. Although the dose of cisplatin was adequate (100 mg/m2), neither ECOG nor other groups give this drug every 4 weeks in other situations. Giving cisplatin with C225 every 4 weeks may be acceptable because of the possibility of combination-induced toxicities.

Anti-EGFR antibodies were also found to exhibit radiosensitization properties in cell cultures and in animal systems experiments when given with radiation therapy. In a phase I study reported by Robert et al,[50] C225 and radiation therapy were given to 16 patients with locally advanced cancers (13 patients with stage IV). They reported a total clinical response rate of 100% and a CR rate of 87% (13 of 16 patients). A phase III randomized trial comparing radiation therapy alone vs radiation therapy plus C225 in patients with locally advanced cancers recently finished accrual. As noted above, the standard treatment for these patients at the time of this study was concurrent chemotherapy-radiation therapy, and remains so today. Again, the results of this randomized trial may be meaningless because of the flawed trial design that used radiation therapy alone as the standard arm. Excellent reviews on targeted therapy in patients with head and neck cancers have been recently published.[51,52]

Properly designed protocols that combine these agents with chemotherapy, radiation therapy, and chemotherapy-radiation therapy should provide an additional positive impact on the results of treatment of this disease.


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