Treatment with cetuximab has been used as a line of therapy for colorectal tumors , refractory non-melanoma skin cancers , and in relapsed head and neck cancers , including as a second or first line of treatment [21, 2322,]. However, oral mucositis has been frankly described as a high-incidence adverse effect during the use of this monoclonal antibody . In our study, the frequency of oral mucositis was 41.0%, quite similar to that described in the literature. Still, this incidence depends directly on the type of tumor treated and the antineoplastic protocol used.
A recent systematic review describes that the incidence of oral mucositis is lower when monoclonal antibodies are used compared to conventional chemotherapies . Still, the incidence increases significantly when chemotherapy is used concomitantly . When used as monotherapy for colorectal cancer treatment, the incidence of oral mucositis does not exceed 10% of patients . During treatment for skin cancer, this adverse effect is not even mentioned as significant [28, 29]. In head and neck tumors, even when used in combination with cisplatin and/or paclitaxel, the incidence of oral mucositis related to cetuximab is 3-4.4% . Still, when associated with radiotherapy, the incidence increases alarmingly to values around that observed in our study (44.7%) .
We also observed a low incidence of oral mucositis in non-head and neck tumors. Similar to what is described in the literature, no cases of skin cancer and only 28.3% of colorectal tumors had oral mucositis related to treatment with cetuximab. On the other hand, patients with head and neck tumors ranged from 22.9 to 89.7% incidence of oral mucositis. The factor most strongly associated with the development of oral mucositis in these tumors is the combination of cetuximab and radiation therapy. In phase I studies, > 70% of patients developed mucositis during the combination therapy , and these values can be as high as close to 100% . In one clinical trial, the incidence of oral dermatitis and mucositis combining cetuximab and radiotherapy was more elevated than conventional treatment combining cisplatin and radiotherapy .
Bonner  state that the addition of cetuximab to radiotherapy significantly improves overall survival, progression-free survival, and loco-regional control if compared to radiotherapy alone. However, treatment with cetuximab seems to show more benefit in tumors with high EGFR expression (> 40%) . Hence, although treatment with cetuximab combined with radiotherapy compared to radiotherapy alone does not significantly interfere with the quality of life of patients being treated for head and neck tumors , its use should be considered based on the overall health status of the patient since the addition of cetuximab to conventional treatments significantly increases the incidence of non-hematologic adverse effects, mainly cutaneous/dermal such as skin rash, hand and foot syndrome, and oral mucositis [37, 24].
Other factors that emerged as risk factors for the appearance of OM, with relevance in this study, were gender and age. The highest prevalence of mucositis was found in females and patients over 70 years of age. Although Nishii et al. (2020) evaluating patients with head and neck cancers showed a higher incidence of oral mucositis in men, several studies have shown that women have an increased risk of oral mucositis during chemotherapy [38, 39]. Female hormones show a complex and sometimes controversial association with local and systemic inflammatory processes and somehow contribute to this increase .
As for age, individuals over 70 years of age have a higher severity of oral mucositis, but there is no cause related to this. In general, young and elderly patients show the same clinical benefit during systemic treatment, but the fragility of health in older patients significantly increases the risk of toxicity . In the present study, age was the major risk factor for oral mucositis related to treatment with cetuximab, and attention should be paid to this fact, as it may be necessary to consider the use of cetuximab in older patients given the increased adverse effects [42, 43, 44].
Severe oral mucositis leads to treatment discontinuation due to painful symptomatology of the lesions and compromises treatment prognosis [26, 25]. In the multivariate analysis of our study, we showed that sex, amount, and size of the dose but especially age are important risk factors for oral mucositis. ALONGI [ 22] and BONNER  describe that the increase in survival of patients with head and neck cancers treated with RT and cetuximab is only modest for patients over 70 years old, so possibly the use of cetuximab in these specific groups (women, over 70 years old and requiring high doses and a large number of cycles) should be highly considered.
Perhaps the most significant limitation of our study is its retrospective nature. It makes it impossible to track important information about prognosis and other adverse effects. However, this study shows critical risk factors to patients taking cetuximab, which may help clinical management during oncological treatment, especially head and neck tumors.