The systematic review by the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO) reported the prevalence of oral candidiasis for all cancer treatments to be 7.5% before starting treatment [17]. This was more than double the increase in comparison to the 3% in our study. We enrolled 97 patients onto the study and 3 patients were excluded due to a clinical diagnosis of oral candidiasis before the study began. MASCC/ISOO also reported that the prevalence of fungal colonization was 48.2% before all cancer treatments [17]. This was comparable to our findings of 39.5%. With an accuracy of clinical candidiasis before treatment at 60%, clinicians need to take into account the fact that oral candidiasis occurs even before any treatment for HNC patients begins, particularly in the patients with significant detrimental risk factors for fungal colonization at baseline, i.e., ex-or current smoker, increasing age, and ex-or current history of betel nut chewing.
MASCC/ISOO reported a weighted prevalence of oral candidiasis during treatment at 39.1% [17] which was in line with the current study at 35.4%. With the focus on the incidence of growth of fungal colonies, 65.9% of patients had confirmed positive cultures for fungal microorganisms in this study. This was slightly lower than a systematic review by the group from MASCC/ISOO [17]. They reported a prevalence of fungal colonization during RT of 74.5%. When considering the clinically diagnosed incidence of oral candidiasis throughout the treatment in this study, the accuracy was as low as 50% and 52% for during and at the end of RT, respectively. Some clinical presentations of erythematous and angular cheilitis forms of candidiasis could be obscured by radiation-induced mucositis. This could be the explanation for the underestimation of clinical diagnosed oral candidiasis during RT. Many studies summarized the clinical appearance of oral candidiasis [12,13,14]. We suggested careful oral examination during RT focusing on the various types of oral candidiasis. Our study also performed an oral/tongue swab at the end of RT. The fungal colonization at the end of treatment was still high, being found to be the same as during RT at a rate of 57.8%. Jham et al. [5] reported an incidence of colonization of 71% at the end of RT. Ramirez-Amador et al. [6] reported the prevalence of positive candida cultures at 62% at completion of RT. These findings were meaningful for the clinicians, highlighting the need to pay close attention and prescribe the necessary interventions at the end of treatment.
In non-pathological circumstances, the most common characteristic oral flora consists of Candida species. Under some physiological and pathological conditions, Candida may change status from that of commensalism to a pathogen [3, 5]. Candida albicans has been identified as being the most frequent species in head and cancer patients in most studies [3,4,5, 7, 8]. Our results are similar showing that C. albicans was the most commonly found species, being as high as 82% throughout the treatment, the second and third most common being non-albicans species; C. tropicalis, and C. glabrata.
Previous studies have reported controversial risk factors of oral candidiasis and colonization in HNC patients receiving RT [5, 6, 9, 18]. Focusing on the clinical diagnosis of candidiasis throughout the treatment, smoking and being female were the independent factors in our study, findings in line with the other research [5, 9]. Epstein et al. [9] found the presence of oral prosthesis, alcohol use, and smoking represent risk factors for oral colonization. Panghal et al. demonstrated that Grade 4 mucositis is the most significant risk factor of oral candida infection [18]. Some studies demonstrated the correlation between xerostomia and the risk of oropharyngeal infection [5, 6]. These findings were in contrast to our study. Even though significance in the univariate analysis was demonstrated with radiation-induced oral mucositis and xerostomia during the treatment, both acute side effects were not significant in the multivariate analysis for the fungal colonization throughout the treatment. Ramirez-Amador et al. reported that smoking and denture wearing were not risk-factors for increased fungal colonization [6]. In this study, we found that increasing age, smoking, and chewing betel nuts were associated with fungal colonization at baseline before the treatment, although throughout the treatment, three factors were significantly related to fungal colonization: the addition of chemotherapy into RT, increasing age, and using a 2% viscous lidocaine solution. RT itself damages the local oral mucosa and salivary glands. These injuries lead to an increase in fungal colonization. CCRT with cisplatin has been found to synergistically induce severe mucosal injury [19]. Increasing age has been reported as one of the risk factors of fungal colonization in many studies [3, 5, 8, 18] and our result were consistent with their findings. It was surprising that using a 2% viscous lidocaine solution was another risk factor for fungal colonization in our study. Three in-vitro studies [20,21,22] supported the efficacy of lidocaine as an antifungal drug. The first study [21] found a dose-dependent fungicidal effect of lidocaine. Another study demonstrated the in-vitro effect of lidocaine on C. albicans germ tube formation [22]. Palmeira-de-Oliveira et al. [20] reported the dose-dependent fungicidal effect of lidocaine with the concentrations varying from 15 to 30 30 mg/ml. They also noticed that different species of candida had different susceptibility to this drug, i.e., C. krusei and C. albicans ATCC10231 responded to lidocaine at a minimum inhibitory concentration (MIC) of 10 mg/mL while other C. albicans needed an increasing concentration [20]. Although we did not use the commercial preparation of 2% viscous lidocaine solution in this study the concentration of the hospital preparation that we prescribed for our patients was at least higher than the MIC to which Candida was susceptible. However, we did not record the level of patient adherence to all prescribed drugs during the treatment including this solution. In view of this, caution must be paid to this finding and we could not strongly conclude that lidocaine solution is one of the risk factors associated with fungal colonization.
As far as we know, this is the first reported study on the accuracy of clinically diagnosed oral candidiasis by confirmation with fungal colonization in HNC receiving both RT alone and CCRT. We tried to analyze all determinants which could be related to fungal colonization before and throughout the treatment, e.g., patient factors, treatment factors, and treatment complications.
There are also some limitations to this study. First, some patients dropped out and did not receive oral/tongue swabs during and at the end of treatment. Second, Benzydamine HCl and 2% viscous lidocaine solution were used as analgesic drugs for treating radiation-induced mucositis in the patients which may have impacted on the data. According to an in-vitro study [21], both local anesthetics showed a supplemental benefit in the treatment of candidiasis. Patients who used either or both drugs might not represent the true rate of fungal colonization during and at the end of RT/CCRT. Third, the levels of patient adherence to 2% viscous lidocaine solution during the treatment were not recorded. Consequently, this study has some inconsistencies in adding weight to the fungicidal effects described in some previous studies [20,21,22]. Hence, the results of 2% viscous lidocaine solution as one of the risk factors in this study should be interpreted with caution. Forth, we prescribed anti-fungal agents immediately for every patient who had only clinically diagnosed oral candidiasis during the treatment, which could not represent an accurate rate of fungal colonization during RT/CCRT and at the end of treatment.