Chemotherapy (Chemo) has become an integral part of potentially curative therapy for head and neck cancer. Che-moradiotherapy (ChemoRT) has been shown to be superior over radiotherapy (RT) alone, in terms of locoregional control and overall survival. Platinum based regimens in combination with 5-fluorouracil have been the most effective chemotherapy regimen so far. Given the toxicity of con-current ChemoRT, careful selection of patients is critical [1-3].

Targeted therapies, which include monoclonal antibodies and small molecule inhibitors, that target specific growth factors and growth factor receptors, have significantly changed the treatment of cancer over the past 10 years. One particular growth factor receptor and signal transduction system that has been shown to play an important role in the pathogenesis of head and neck cancer is the epidermal growth factor receptor (EGFR) and its ligand. Ligand binding to EGFR results in activation of tyrosine kinase pathways that significantly affect tumorigenesis by stimula-ting cell proliferation, inhibiting apoptosis and favoring angiogenesis to facilitate metastasis.

EGFR is overexpressed (80-100%) and/or abnormally activated in head and neck cancers, correlating with poor clinical outcome in these patients [4-6]. Inhibition of the EGFR-induced signal transduction pathways by monoclonal antibodies has been shown to inhibit the growth of EGFR-expressing human cancer cells.

Cetuximab (C-225, Erbitux®), is an IgG1 subclass mouse-human chimeric monoclonal antibody, which binds with high affinity to the extracellular ligand binding domain of the receptor, leading to inhibition of cancer cell prolife-ration, invasion and migration.

Cetuximab competes with natural legands of EGFR for binding to the receptor and thus, prevents activation of the receptor. In addition, cetuximab might trigger the internaliza-tion and degradation of the receptor. An antineoplastic effect mediated by immune mechanisms has also been postulated, specifically by the induction of antibody-dependent cell-mediated cytotoxicity [7].

On the other hand, EGFR is also expressed in normal epithelial cells (of skin and mucosa), thus, EGFR inhibition can lead to significant dermatologic and gastrointestinal toxicities.

Several studies and clinical trials have been conducted to investigate the effect and safety of cetuximab used for the treatment of locoregionally advanced and/or recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma, in terms of locoregional control, free-disease survival, and overall survival [8-7].

Cetuximab has been used alone and in combination with platinum-based chemotherapy [9-1, 13] or in combination with platinum-based chemotherapy and 5-fluorouracil (5-FU) [12, 14, 17]. Cetuximab has also been used in combina-tion with radiotherapy [8, 15, 16].

Cetuximab has been found to be well tolerated and active. A superior overall survival, progression-free survival and locoregional control, attributed to cetuximab, have been reported [14-17].

When cetuximab was added to platinum-based chemo-therapy and 5-FU, there was no significant difference in the overall incidence of grade 3 or 4 adverse events between the groups [14]. The addition of cetuximab had no impact on the Quality of Life, as it was assessed with the QLQ-C30 and QLQ-H&N35 questionnaires. Furthermore, patients in the cetuximab arm displayed significant improvements in pain, swallowing problems and scores for speech and social eating problems [17].

Skin reactions, particularly an acne-like rash, as a result of the normal expression of EGFR in the skin, are the most common cetuximab-related adverse events, in cetuximad and chemotherapy combinations, reported in more than half of the patients, mainly grade 1 and 2 [9-4, 17].

The combination of cetuximab and radiotherapy in patients with locoregionally advanced head and neck car-cinoma, did not increase the common toxic effects associated with RT, including oral mucositis, xerostomia, dysphagia, oral pain/odynophagia, weight loss and performance status deterioration [8, 15, 16].

The addition of cetuximab did not adversely affect the quality of life. This was particularly notable for global health status/QoL, social functioning, social eating and social contact [16]. Acneiform rash was found to cause a dose reduction in less than 5% of the patients.

In contrast to the previously documented efficacy and safety of cetuximab, Pryor et al. [18] reported that the addition of cetuximab to radiotherapy, administered to 13 patients, with locally advanced head and neck carcinoma and major co-morbidities, including dysphagia and significant weight loss prior to the commencement of therapy, resulted in a high rate of toxicity, associated with low treatment compliance and delays in completing RT. Grade 3 oral mucositis developed in 10 patients (77%) frequently in areas that had received less than 10-15Gy, most commonly the mucocutaneous junction of the lips.

The mucocutaneous junction of the lips is, however, the site of predilection of herpes simplex virus-1 (HSV-1) reactivation and infection (Herpes Labialis). Herpes simplex virus-1 reactivation and infection is frequent in cancer patients [19] and can, often, complicate the ulcers of oral mucositis, increasing the severity of mucositis [20, 21]. Accordingly, HSV-1 infection could be related to the severe mucositis on the mucocutaneous junction of the lips in those 10 patients reported by Pryor et al. [18].

Significant adverse effects, including one myocardial infarction, one bacteremia, one atrial fibrillation, and two deaths (one of pneumonia) were also reported when cetuximab was administered concurrently with radiotherapy and platinum-based chemotherapy in 22 patients, with predominantly stage IV squamous cell carcinomas of the head and neck, although preliminary efficacy was encoura-ging [22]. The study was closed because of significant adverse events. The potential microbial systemic dissemina-tion from the oral cavity in patients with advanced cancers and co-morbidities was not considered. As it is known, the oral mucosal barrier damage and the development of oral ulcerative mucositis may allow for the development of local and / or systemic fungal or viral or bacterial infections.

Severe oral ulcerative mucositis, grade 3 or 4, is a major limitation to continuous, uninterrupted RT and concurrent chemotherapy in the management of head and neck cancer. Nearly all patients (90-97%) with head and neck cancers receiving RT or chemoRT will experience some degree of mucositis [23-25]. Over 50% of these patients may expe-rience severe, grade 3-4 mucositis, associated severe pain, dysphagia and severe weight loss, which compromises patient’s quality of life. Higher grades of ulcerative mucositis are also related to higher frequency of radiation treatment breaks with adverse effect on tumor control [26, 27].

In addition, mucositis has a major economic impact due to costs associated with pain management, liquid diet supp-lements, gastrostomy tube placements or total parenteral nutrition, management of secondary infections and hospita-lizations [28, 29].

Local infections, candidiasis and herpes simplex may complicate the clinical course of oral mucositis, while oral flora colonizing the mucosa may lead to secondary poten-tially life threatening systemic infection [30-32], especially in compromised patients, with advanced or metastatic cancer.

The most common and well studied infection of the oral mucosa during head and neck cancer RT is oral candidiasis, reported with an incidence of 27%-53% [20, 33-36].

Oral candidiasis develops superimposed on mucostis, in a Candida carrier, potentially adding to the severity of mucositis. Candida carriage prevalence, in head and neck RT, varies between 50% to 70% [36-38]. Systemic adminis-tration of fluconazole prophylaxis has prevented candidiasis, and has significantly reduced the Candida carriage and the severity of oral mucositis and RT interruptions [36, 39, 40].

Herpes simplex virus-1 (HSV-1) reactivation, both before and after cancer therapy, has been reported to be frequent. Patients, who received cancer therapy and were found HSV positive with direct immunofluorescence, seemed to have more severe oral mucositis than HSV negative patients, while a positive IgM result was more frequent in the mucositis group of patients [19].

Herpes simplex virus-1 infection in radiation-induced oral mucositis, complicating the severity of mucositis has been shown in our head and neck cancer patient population [20, 21]with an incidence of 29%. HSV-1 infection has been observed to aggravate mucositis.

Based on the presented data of the high incidence of candidiasis, and Candida carriage, the risk of infection recurrences, as well as the high risk of HSV-1 reactivation and infection and the infections’ potential role in the severity of oral mucositis, combined with the difficulty in the differential diagnosis of mucositis from infections [21, 36], systemic antifungal and antiviral treatment and prophylaxis has been introduced to our head and neck cancer patient population as a routine clinical practice, since 2005.

The purpose of this report was the assessment of oral toxicity in head and neck cancer patients who received cetuximab, added to radiotherapy and platinum-based che-motherapy. The oral toxicity was prospectively evaluated in 24 head and neck patients and was compared to that of 25 patients, who received RT with platinum-based chemother-apy alone, in the years 2007 and 2008. The patients, in both arms, received antifungal and antiviral treatment and prophylaxis.

The present observations, which were collected pros-pectively, in a consecutive patient cohort, “out in the real world”, during the routine chemoradiotherapy schedule, outside the context of a clinical trial, showed that the addition of cetuximab in the chemoradiotherapy scheme did not increase the oral toxicity.

The incidence of severe oral mucositis, objectively observed, by Oral Medicine specialist, and severe pain and xerostomia, self-reported by the patients, in group B, who received RT, cisplatin and cetuximab, did not differ significantly, when compared to those of Group A, who received RT and cisplatin, both during and after the completion of chemoRT.

The RT unplanned breaks and the RT interruptions due to severe mucositis did not differ significantly between the two patient groups, either.

Similar numbers of patients, in both groups, received antifungals and antivirals. The use of anti-infectious medi-cations, being similar in the two groups, further indicated, though indirectly, that cetuximab did not increase the local, mucosal toxicity, since oral mucosal infections consist a significant part of oral toxicity in cancer patients [19-21, 33-38, 42].

The prevalence of severe oral mucositis, pain and xerostomia observed during the course of chemoRT were significantly reduced in both groups after the completion of chemoRT, attributed to the administration of antifungal and antiviral treatment and prophylaxis, as has peviously been shown [20, 21, 36, 39, 40].

The patients, in the two groups, did not differ signi-ficantly in most characteristics, such as the gender, age, tumor histological diagnosis and tumor size.

The numerical difference in the median age, although not significant, represents a weakness, which is related to the non-randomized controlled study design. It is not known how or whether the younger age of the patients in Group B as opposed to Group A (57 vs. 63 years) could have affected the oral toxicity and the tolerance of the patients to the combination of cetuximab, cisplatin and RT.

The significantly higher number of patients in group B (cetuximab, cisplatin and RT) without nodal involvement as opposed to Group A (8 vs. 2 patients) represents another weakness of the non randomized study design. On the other hand, significantly more patients from Group B were irradiated with a 2.0Gy daily RT dose (20 vs. 8 patients). The limited number of patients in both groups did not, however, allow for further comments and evaluations.

Cetuximab was well tolerated in our patients, as in previous reports, where cetuximab was added to RT [8, 15, 16] or to platinum-based chemotherapy [9-1, 13] or to platinum-based chemotherapy and 5-FU [12, 14, 17] and it did not increase the common toxic effects. Significant adverse effects, as they had been previously reported when cetuximab was administered concurrently with radiotherapy and platinum-based chemotherapy [18, 22], were not observed in the present study.

Interestingly, a great majority of patients in both groups (76% from Group A and 62.5% from Group B) were in the advantageous tumor size T1 or T2 of their cancer. Further-more, all patients were not previously treated and had no serious co-morbidities. This is in contrast to the patients of previous reports, who had locoregionally advanced head and neck cancer or previously treated recurrent and/or metastatic cancer, with potentially compromised nutrition and well being [8-7, 18, 22]. Although, as is generally accepted [1], careful selection of patients is critical in chemoRT, the extent to which the early stage of the cancer patients in the present report might have influenced toxicity, cannot be evaluated in this setting. It would be interesting to assess, in a next step, given the increasing use of cetuximab, whether patients with different stages in their cancers exhibit different tolerance values and toxicities after cetuximab administration.

Seventy per cent of the patients of both groups, in the present study, received antifungals and antivirals during the course of chemoRT, according to the policy of our Center. The need and the use of antifungals and antivirals have not been mentioned in the previous reports [8-7, 18, 22].

Local, oral mucosal infections and their potential sys-temic dissemination, especially in patients, compromised with advanced cancers, previous treatments and serious co-morbidities, were not clearly ruled out in previous studies.

The severe adverse effects reported by Pfister et al. [22], could be related, at least in two of the cases (bacteremia and pneumonia), to systemic infection disseminated from a possible oral site-mucosal infection, superimposed on oral mucositis, while HSV-1 infection could be the cause of severe labial toxicity reported by Pryor et al. [18]. In addition, 3 of the 13 patients reported by Pryor et al. [18] had dysphagia and severe weight loss before the commen-cement of treatment.

The high incidence of rash and dermatitis of our patients (62.5% of the Group B) is in agreement with the recent report by Giro et al. [43]. The acne-like rash and dermatitis, observed in our patients was adequately managed, according to the suggested guidelines [41]. Severe skin reactions as reported in the cases by Berger et al. [44]and by Budach et al. [45] were not observed.

In conclusion, no statistical differences for the toxicities under study were observed. Cetuximab did not increase the severity of the oral mucositis, pain and xerostomia in head and neck cancer patients, who received chemoradiotherapy, with limitations of the current study design and its limited number of patients. A large-scale randomized controlled trial is needed to confirm the above results.

Risk factors, including co-morbidities and the extent of locally advanced head and neck cancer stage, potentially compromising the patient, and other factors should be studied, identified and taken into account, in order to use cetuximab at an optimal setting for the optimal patient benefit.