New therapies in squamous cell carcinoma of the head and neck: is the future in combined therapies?

Abstract

Every year there are more than 500,000 new cases of head and neck cancer throughout the world, primarily squamous cell carcinoma. For stage I and II cancers, surgery and radiotherapy allow progression-free survival for 5 years in 60% to 90% of the cases, depending on its localization. However, more than 50% of patients have advanced lesions at the time of diagnosis and will have local recurrence and distant metastasis.At the end of the 1970s, cisplatin was the first product to demonstrate a significant effect on this type of cancer, with a 30% objective response rate. Al Sarraf et al.'s [1] protocol associating cisplatin and 5-fluorouracile (5Fu) in a neoadjuvant setting gave a clinical objective response rate of 90%, with a 25% complete response rate. Yet randomized trials demonstrated that, with a few exceptions, although this induction chemotherapy lowers the rate of distant metastasis, it does not significantly increase survival and its indication must take into consideration organ preservation, notably for the larynx.A number of randomized trials have shown that radiochemotherapy either concurrently or alternately associating a platinum compound or its combination with 5Fu with radiotherapy was more effective than radiotherapy alone and significantly increased survival [2]. Recently, taxanes were shown to be active and the association of docetaxel and cisplatin-5Fu proved to be more effective than the traditional combination of cisplatin-5Fu. Current trials show that induction chemotherapy using the triple combination followed by radiochemotherapy is more effective than radiochemotherapy based on cisplatin alone. However, this regime also shows high toxicity, particularly hematological toxicity.Targeted therapies are now providing new hope [3]. We are beginning to understand the role of growth factors, their receptors and signaling pathways in the cancer genesis and progression. Epidermal growth factor receptor (EGFR), a member of the HER1 family, is overexpressed in more than 90% of squamous cell carcinoma of the head and neck (SCCHN). Overexpression of EGFR or of its main ligands, EGF and transforming growth factor alpha (TGFα), indicate an unfavorable prognosis. As a result, EGFR is considered to be a potential target for these new therapeutic approaches. There are several monoclonal antibodies and tyrosine kinase inhibitors (TKIs) that target EGFR and its mutated forms.Cetuximab (IMC 225) was the first monoclonal antibody used. It is a human/murine lgG1 chimeric antibody that binds more to the EGFR extracellular domain than to its EGF and TGFα ligands. It has antitumor activity on its own and creates synergies with chemotherapy and radiotherapy. The most frequent side effects are fever, asthenia, nausea, transaminases increase and, particularly, skin toxicities in the form of rashes. A recent study on numerous patients with stage III and IV SCCHN clearly indicated that the association of radiotherapy and cetuximab very significantly increased local control and survival when compared with radiotherapy alo...