Cancers arising from the head and neck region are a diverse group of malignancies that include paranasal sinus tumours, salivary gland tumours and malignancies of the lip, oral cavity, oropharynx, hypopharynx, larynx and nasopharynx. Head and neck cancer has an annual global incidence of over half a million cases and remains the fifth most common cancer worldwide. Of these cases, the majority are head and neck squamous cell carcinomas (HNSCC).

Traditional therapy of HNSCC has involved a multimodality approach employing surgery, radiotherapy and chemotherapy. This last decade has seen the integration of chemoradiotherapy with improvements in quality of life, organ preservation and survival. Nevertheless, most patients with Stage III or IV disease, and nearly all patients with recurrent or metastatic disease will succumb to their illness.

The benefits of conventional therapy are beginning to plateau such that ongoing improvement in outcome for these patients will depend on advances in surgical techniques, radiotherapeutic techniques and molecularly targeted therapies.

Role of molecular targeted therapy
Cancer results from aberrations in genetic and epigenetic processes, both of which are paramount for cellular function, differentiation, survival and proliferation. Molecularly targeted agents offer attractive therapeutic options by restoring normal control of oncogenic processes.

The epidermal growth factor receptor (EGFR) and its ligands {epidermal growth factor (EGF) and tumour growth factor (TGF- α)} are fundamental for cell proliferation, motility, adhesion, invasion and angiogenesis. By dysregulating the EGFR signal transduction pathways, the process of tumour formation, growth and metastasis occurs. Both biochemical and immunohistochemical studies have demonstrated expression of EGFR in a number of solid tumorus, including 80-90% of HNSCC, 1-3 and elevated levels of EGFR protein have been shown to be a poor prognostic factor 2-4 .

EFGR inhibition has proven to be an important strategy in the treatment of HNSCC as well as other cancers of the head and neck. Although EGFR is the best understood and studied target in HNSCC, other molecular targets such as vascular endothelial growth factor (VEGF) and ErbB2 are also undergoing further evaluation.

Targeting EGFR
The use of anti-EGFR therapies is the most employed molecular-targeted strategy studied in HNSCC. The rationale for their use stems from EGFR biology in HNSCC. Preclinical work has shown the importance of EGFR in the pathogenesis of HNSCC. Messenger RNA for both EGFR and its ligand EGF are found to be elevated and overexpression of EGFR protein is seen in up to 47% of HNSCC.

Levels of EGFR are also increased based on stage and grade of the tumour. Upregulation of EGFR is further observed as cells change from dysplasia to squamous cell carcinoma. Based on these observations, several Phase II studies have sought to establish response to targeting the EGFR (Table 1).

Both small-molecule tyrosine kinase inhibitors gefitinib and erlotinib have been evaluated in Phase II clinical trials.

Cohen et al. reported on the single agent activity of gefitinib at both 500mg/day and 250mg/day. At a dose of 500mg/day, the observed response rate was 10.6% and the disease control rate was 53%, whereas at a dose of 250mg/day, only a 1.4% observed response was noted and the disease control rate was 34%.

Wheeler et al. evaluated gefitinib in patients with recurrent HNSCC and stratified them into two groups; group 1 included patients who had not been treated for their recurrent disease and group 2 included patients who had received only one treatment regimen. Only patients who did not receive prior therapy for their recurrent disease responded to treatment (15% response rate) and the overall survival for all 32 patients was 6 months.

Soulieres et al. evaluated erlotinib in 115 patients with recurrent or metastatic disease and reported an overall objective response rate of 4.3% and disease stabilization rate of 38%.

Cetuximab, a human-murine chimeric IgG monoclonal antibody that binds to the extracellular domain of EGFR has been used in Phase II trials in patients with recurrent or metastatic HNSCC as a single agent or in combination with chemotherapy. Phase I studies showed no overlapping toxicities when combined with full dose cytotoxic agents. A Phase II study of cetuximab alone in patients who progressed on platinum-based therapy, documented a response rate of 13%; however, overall survival was still <6 months. Table 2 summarizes some of the phase II studies evaluating the use of cetuximab in patients with recurrent or metastatic HNSCC.

So far, only two published phase III randomized clinical trials have incorporated a targeted therapy into the treatment of HNSCC. In one of these studies, patients with loco-regionally advanced HNSCC were randomly assigned to radiotherapy alone or radiotherapy plus cetuximab. Patients were ineligible if they had previously undergone surgery or had previously received radiotherapy for head and neck cancer. Between the two arms of the study, 424 treatment-naïve patients were enrolled and results showed a median duration of loco-regional control of 24.4 months versus 14.9 months (p = 0.005), favoring the addition of cetuximab. Of importance, the median duration of overall survival was 49.0 months versus 29.3 months (p = 0.03), again significantly favoring the additional use of cetuximab. The Eastern Cooperative Oncology Group (ECOG) has also recently completed a phase III trial comparing the use of cisplatin plus placebo versus cisplatin plus cetuximab in patients with recurrent or metastatic disease. These patients were not previously treated for their recurrent or metastatic disease. Based on 117 analyzable patients, those treated with cetuximab plus cisplatin had statistically superior objective response rates (26% versus 10%, p = 0.03) but not median progression-free survival (4.2 months versus 2.7 months, p=0.09) or overall survival (9.2 versus 8.0 months, p = 0.21).

Other strategies under evaluation
Beyond just targeting EGFR, two studies have recently evaluated the role of lapatinib, a selective and potent dual competitive inhibitor of EGFR and ErbB2.

Harrington et al. report on a Phase I study of lapatinib plus chemoradiation in patients with locally advanced HNSCC and Abidoye et al. report on a Phase II trial of lapatinib in recurrent or metastatic HNSCC.

The Phase I study confirms the safety of the combination of lapatinib, cisplatin and standard radiotherapy; however, the Phase II trial showed the drug to have no activity. Other preliminary trials have evaluated antiangiogenic drugs.

A Phase II study of sorafenib, a potent inhibitor multiple receptor tyrosine kinases and serine-threonine kinases including Raf isoforms. VEGFR-2 and PDGFR-, in patients with recurrent or metastatic HNSCC and nasopharyngeal cancer has shown a partial response in 1 out of 23 and stable disease in 9 out of 23 patients.

Finally, Vokes et al recently presented a Phase I/II study of bevacizumab and erlotinib in 55 patients. Overall response rate was 14.6%, with two complete responses observed. Survival data from this study is in keeping with prior studies and the median survival was 6.8 months.

Conclusion
The increased knowledge of the molecular alterations present in HNSCC has led to efforts to develop compounds that target these molecular pathways. As EGFR is overexpressed in HNSCC, different strategies to target this activated receptor have reached the clinic. Among them, a monoclonal antibody termed cetuximab and two low-weight tyrosine kinase inhibitors (gefitinib and erlotinib) have shown promising results.

For instance in the treatment of locally advanced HNSCC, cetuximab increases the activity of radiotherapy. In the metastatic setting, cetuximab increases the activity of chemotherapy compounds. Other drugs against the EGFR and other molecular pathways are in preclinical and clinical development. From all of these, anti-VEGF therapies are promising agents especially in combination with other chemotherapy or targeted agents.

Although these are exciting new advances, important questions remain. Criteria for adequate patient selection for these targeted therapies remain unanswered as well as the best way to increase the activity of these agents.

In conclusion, several compounds have now reached the clinic with successful results. In the future, these therapies and others to come will need to be integrated in a rational way with standard treatments. This will hopefully improve the prognosis of HNSCC.

Table 1. EFGR tyrosine kinase inhibitor trials in HNSCC patients



Table 2. Trials using anti-EGFR antibodie in HNSCC patients

Dr Joanne Ngeow
Registrar

Tan Eng Huat
Senior Consultant

Medical Oncology
National Cancer Centre Singapore

Click [ here ] for references of key studies.