DISCUSIÓN

Cyclooxygenase-2 (COX-2) and epidermal growth factor (EGF) in oral premalignant epithelial lesions

Ciclooxigenasa-2 (COX-2) y el factor de crecimiento epidérmico (EGF) en lesiones epiteliales orales premalignas

Mario Fernando Muñoz Guerra

Servicio Cirugía Oral y Maxilofacial. Hospital Universitario de la Princesa. Madrid. España

Squamous-cell carcinomas of the oral cavity are a group of diseases that still have a considerable incidence and high mortality rate. This is somewhat paradoxical because most intraoral tumors are preceded by easily detectable changes in the characteristics of the mucosa, particularly lesions of the leukoplakia or erythroplakia type. At present, despite the vast amount literature available on the topic, we cannot define reliable risk markers for the assessment of these putatively premalignant lesions.

The authors of this article have extensively reviewed the literature centering on two biomarkers of special relevance at present in the treatment of squamous-cell carcinoma of the head and neck. Lamentably, they do not discuss how an experimental study of these markers would help to clarify this issue. However, the bibliographic information addressed here raises two important questions of very different nature: 1) What is the prognostic importance of the presence or increase in the expression of these biomarkers? 2) Does the discovery of drugs that block these substances or their receptors at the cellular level have any therapeutic utility? With regard to these two questions, the literature reveals notable discrepancies in the case of COX-2 and EGFR.

Few doubts persist about the occurrence of COX-2 overexpression in squamous-cell carcinoma of the head and neck and in premalignant lesions. Important investigations support this finding.^1,2 More doubts exist regarding their true therapeutic utility. Evidence from studies in vitro and in animal models suggests that COX-2 inhibition can suppress carcinogenesis by acting on certain pathways of COX-2 inhibition, promoting apoptosis (programmed cell death), and inhibiting angiogenesis.³ The Norwegian author Jon Sudbo published a noteworthy study in 2005 in Lancet. This study of a cohort of 9421 subjects was undertaken for the purpose of showing that the use of nonsteroid anti-inflammatory agents (COX-2 inhibitors) produces a long-term reduction in the incidence of oral cancer.⁴ Unfortunately, the study was shown to be one of the foremost scientific frauds in recent years, arousing bitter controversy in the scientific community about the true reliability of many studies, including those published in journals of international prestige. In addition, certain publications have suggested the utility of certain therapies based on the use of COX-2 inhibitors that we might consider "outlandish". For example, Sood et al.⁵ have suggested that topical nonsteroid anti-inflammatory use could help to prevent oral cancer. The controversy that has developed around COX-2 inhibitor medications has made it unlikely that a serious prospective study using a control group can be conducted, as would be desirable to validate the true clinical utility of these therapies.

Such a study would be more feasible in the case of EGFR inhibitors. Amplification of interest in this factor has been observed in numerous publications focusing on oral squamous- cell carcinoma and premalignant lesions.^6,7 Overexpression of these factors has been observed with a frequency of 80-100% in premalignant lesions, generally associated to a less favorable prognosis for disease outcome.8 ZD1839 (Iressa^®, or gefitinib) and OSI-774 (Tarceva^®, or erlotinib) are tyrosine kinase inhibitors that have shown promising antitumoral activity. Phase II studies of both compounds conducted in patients with recurrent squamouscell carcinoma of the head and neck have yielded response rates of about 10% of cases.^9,10

The utility of gefitinib has been demonstrated in oral cancer cell lines,¹¹ but the results obtained in clinical applications are inconclusive.^9,12 EGFR activation stimulates certain transcendent signaling pathways in tumor development and progression and influences the resistance to irradiation in an especially important way. Preclinical studies have demonstrated the utility of combining medications that block EGFR with conventional cytotoxics and radiotherapy,¹³ which also reduces the side effects of conventional chemotherapy regimens. These studies have been followed by clinical studies to assess the importance of EGFR expression in oral tumors treated by surgery and adjuvant irradiation.¹⁴ A recent randomized multicenter clinical trial (the first phase III study) focusing on therapy with cetuximab (Erbitux^®, an EGFR inhibitor) has shown the usefulness of this medication in combination with cisplatin and 5-FU, together with coadjuvant irradiation, as treatment for locally advanced carcinoma of the head and neck.¹⁵ The results of this study notably raised expectations on the eve of their presentation to the Congress of the American Society of Clinical Oncology (Chicago, June-2007). This presentation was expected to clarify the true utility of these novel therapies, which may become an interesting adjuvant for oncologic surgery.

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