Abstract

Background: Patients undergoing radiotherapy for head and neck cancer are at increased risk of developing oral candidiasis. The objective of this study was to investigate the clinical Candida mucositis and interruptions in radiotherapy in patients suffering from head and neck cancer, receiving fluconazole in comparison with a control group without specific prophylaxis.

Methods: Eighty consecutive patients were randomized in a prospective double-blind trial of prophylactic oral fluconazole or treatment with the same drug when mycotic infections appeared. Adult head and neck cancer patients who were undergoing treatment with radiotherapy and/or chemotherapy, radiotherapeutic coverage of the entire oropharynx and oral cavity at least 3 cm anterior to the retromolar trigone and receiving a total dose of more than 6000 cGy and Karnofsky Performance Status (KPS) >70 were included in the study. Group A received radiation therapy plus fluconazole (Fluzole 100 mg/day) starting from the sixth irradiation session throughout the treatment; 40 patients in group B received the same baseline treatment, but were given fluconazole only when mycotic infections appeared.

Results: We evaluated 37 patients in group A and the first 37 patients were evaluated in group B. Three of the patients in group A (8.1%) and 14 of the patients in group B (37.8%) demonstrated clinical candidasis. Radiotherapy was interrupted in all of these patients. The differences between the two groups were statistically significant with respect to clinical candidiasis (P = 0.005). The median discontinuation time was 5 days (range, 3–7 days) in group A and 7 days (range, 4–10 days) in group B. The median dose resulting in clinical candidiasis was 3200 cGy (range, 2200–5800 cGy) in all groups. In the fluconazole group it was 4200 cGy and in the control group 2800 cGy.

Conclusion: These results suggest that patients undergoing head and neck radiation therapy are at risk of developing candidiasis and that fluconazole may be used to reduce the frequency of mycotic infections and to improve the radiotherapy schedule in head and neck cancer patients.

Received June 10, 2002; accepted November 13, 2002

INTRODUCTION

Radiotherapy-induced hyposalivation encourages oral candidal colonization that often leads to oral/pharyngeal candidiasis (1). Patients undergoing radiation therapy for head and neck cancer are at increased risk of developing oral candidiasis. Compromised salivary function secondary to destruction of glandular tissue by radiation is thought to be a major factor leading to Candida infection (2,3). Rossie et al. (4) found an increase in colonization and an increase in the risk of clinical infection during radiation therapy. After radiation therapy, the Candida species colonized approximately half of patients (46). Patients who received higher total doses of radiation and doses treated with bilateral fields that included the salivary glands were at greater risk of candidiasis (4). This infection is marked by oral pain and/or burning and can lead to significant patient morbidity that requires management during and after radiation therapy and it is important in immunocompromised patients with cancer when local extension of infection and systemic infection may result in morbidity and mortality (2,7,8). Many such patients may develop mycotic infections which may lead to discontinuation of irradiation with possible consequences for the local control of these cancers (9).

Fluconazole is a new orally absorbed antifungal azole which is effective in the treatment of mucosal and systemic infections caused by Candida, Cryptococci and other fungi. In view of its favourable efficacy, safety and pharmacokinetic profile, it was considered appropriate to evaluate its use prophylactically in patients undergoing a period of neutropenia (10).

The aim of this study was to investigate symptomatic clinical Candida stomatitis and resulting interruptions in radiation therapy in 80 patients suffering from head and neck cancer, receiving fluconazole (Fluzole, Biopharma Drug Company, Turkey) in comparison with a control group without fluconazole prophylaxis.

PATIENTS AND METHODS

This study had the approval of the local study review board. Male and female patients, 18 years or older, with head and neck cancer undergoing treatment with radiotherapy and/or chemotherapy, radiotherapeutic coverage of the entire oropharynx and oral cavity at least 3 cm anterior to the retromolar trigone and receiving a total dose of more than 6000 cGy and Karnofsky Performance Status (KPS) >70 were included in the study. Exclusion criteria were as follows: the presence of oral lesions, such as stomatitis, ulcers, necrosis or candidiasis, a history of allergy to azole antifungal agents, abnormal liver function tests, inability to accept oral intake, lack of cooperation on the part of patients and patients having another systemic disease.

Patients who had given written informed consent were entered in a prospective randomized double-blind trial of prophylactic oral fluconazole or treatment with the same drug when mycotic infections appeared.

Before starting radiotherapy, each patient was given a complete clinical dental examination. They also received a thorough dental prophylaxis, detailed oral hygiene instructions and any necessary dental restorations. Eligible patients were randomized in two groups: 40 patients in group A received radiation therapy plus fluconazole (Fluzole 100 mg/day) starting from the sixth irradiation session throughout the treatment; 40 patients in group B received the same baseline treatment, but were given fluconazole only when mycotic infections appeared. By the end of the first week of a fractionated course during which 1000 cGy are administered, the patient will often complain of tenderness and edematous problems. For this reason, in our study we administered fluconazole prophylactically beginning at the sixth irradiation session. We evaluated 37 patients in group A. Three patients were excluded, two of whom did not use fluconazole properly and one who gave up radiotherapy. In group B the first 37 patients were evaluated.

The median age was 50 years in group A (range, 19–70 years) and 52 years in group B (range, 22–71). A thermoplastic mask and neck rest was initially used for immobilization in all patients. Radiotherapy was administered using cobalt-60 (Picker C 9, USA) at 80 cm SSD. Parallel opposing lateral facial fields and an anterior neck field were used with treatment daily with a mid-plane radiation dose of 200 cGy to a total of 6000–6800 cGy in 30–34 treatment sessions. The spinal cord dose was restricted to be <4400 cGy. A boost therapy of 1600–2400 cGy was given to residual disease at the primary site. Shielding blocks were placed individually if necessary. The treated area included more than half the parotids, the entire submandibular sublingual and most of the minor salivary glands in locally advanced supraglottic larynx cancers.

A swab was taken from the tongue of each patient prior to and once a week during radiotherapy. The swabs were cultured on Sabourauds dextrose agar. Yeast viable counts were evaluated after 48 h of incubation at 30°C. Each organism was identified using the API 20C AUX system (Biomerieux, France) and conventional yeast identification methods using carbohydrate assimilation tests and germ tube formation (11).

Clinical evaluation of patients used a previously described mucositis scoring index (12) as follows:

Estimation of mucositis

Grade Sign and symptoms

0 No ulcerations

1 1 or 2 small (<1 cm) mucosal ulcerations

2 More than 2 small mucosal ulcerations

3 2 or more larger (>1 cm) mucosal ulcerations

4 Multiple mucosal ulcerations

Statistical analysis was performed using the SPSS (Statistical Package for Social Sciences, Windows version 10.0) packed program. The statistical comparison of results was performed by using paired samples, chi-squared/Pearson and Fisher’s exact tests.

RESULTS

From January 1999 to October 2001, 80 patients were randomized in a double-blind method to receive either prophylactic oral fluconazole or treatment with the same drug when mycotic infections appeared.

Fluconazole (Fluzole) was well tolerated in all patients and no early or late toxicity was observed. The clinical characteristics, treated sites (included the oral cavity and/or major salivary glands), treatment doses and volumes were similar in the two groups of patients.

In all, 18 patients (eight in group A, 10 in group B) were administered chemotherapy concurrently with radiotherapy. As chemotherapeutic drug cisplatin 40 mg/m2 per week was used during radiotherapy (Table 1).

We evaluated as symptomatic clinical candidiasis patients with grade 3–4 mucositis and oral microbial assessments confirmed yeast. We interrupted radiotherapy in these patients. No patient received radiotherapy with interruption despite clinical candidiasis.

Before radiotherapy, Candida colonization was observed in 11 of 40 patients (27.5%) in group A (fluconazole) and 10 of 40 patients (25%) in group B (control). The Candida colonization frequency was not statistically different between the two groups. After radiotherapy, Candida colonization was observed in eight of 37 patients (21.6%) in group A and 24 of 37 patients (64.8%) in group B. The differences between the two groups were statistically significant (P = 0.0001). The median dose resulting in clinical candidiasis was 3200 cGy (range, 2200–5800 cGy) in all groups. In the fluconazole group it was 4200 cGy and in the control group 2800 cGy (Table 1).

Three patients in group A (8.1%) demonstrated clinical mycotic mucositis and radiotherapy was interrupted. In 14 of the patients in group B (37.8%) symptomatic mycotic mucositis was observed and radiotherapy was interrupted. The differences between the two groups were statistically significant in respect of clinical candidiasis (P = 0.005). The median discontinuation time was 5 days (range, 3–7 days) in group A and 7 days (range, 4–10 days) in group B.

The yeasts most frequently isolated were Candida albicans in 10 patients. C. tropicalis was detected in three patients, C. glabrata in three patients and C. psudotropicalis in only one patient.

Three patients in the control group and one patient in the fluconazole group who had oropharyngeal streptococcal infection during radiotherapy were treated parenterally with penicillin and radiotherapy was interrupted.

DISCUSSION

The opportunistic fungus C. albicans is the commonest of the Candida species found within the oral cavity while other species which have been isolated include C. glabrata, C. tropicalis, C. kefyr, C. krusei and C. guilliermondii. Candida organisms, as commensal members of the normal oral microbiota, are present on average in 40% (range, 20–40%) of the human population (13). Our findings were similar to those of MacFarlane et al. (13). The primary oral source of C. albicans is considered to be the dorsum of the tongue and other oral sites such as mucosa and plaque-covered tooth surfaces are colonized secondarily (14).

In patients who receive radiation therapy the most common clinical infection of the oropharynx is candidiasis. During radiation therapy Candida species colonize in an increasing number of patients; there is an increase in quantitative counts and an increase in clinical infection (4,6,15,16). We also found a significantly higher Candida colonization rate in the control group than in the fluconazole group after radiotherapy.

Oral mucosa in the path of radiation responds in a manner which correlates with the dose and duration of therapy. As mucosal cells turn over rapidly, they have a low resistance to radiation. The stomatitis associated with radiotherapy probably results from the direct effects of radiation, combined with a species overgrowth of the normal oral microorganisms. By the end of the first week of a fractionated course during which 1000 cGy are administered, the patient will often complain of tenderness and edematous problems. After a 3-week treatment course at 3000 cGy, most oral tissues swell and both vascular and extravascular structures become more permeable. Patients experience pain and burning in the mouth when eating, particularly when spicy or rough-textured foods are chosen (17). The median radiation dosage at which clinical candidiasis occurred was 2800 cGy, similar to that in other studies. This dosage was higher in the fluconazole group (median, 4200 cGy).

Both bacteria and fungi are opportunistic invaders of these compromised tissues. Severe fungal overgrowths, usually of C. albicans, are often observed in the mouths of patients during radiation therapy (17). C. albicans was the most commonly seen fungus (59% of our patients).

In a cohort of patients who were followed through a course of radiation therapy, Candida colonized in 22% before therapy and in 59% by the end of or after radiation therapy (6). In our study, Candida colonization was found in 27.5% of patients in the fluconazole group and 25% in the control group before radiotherapy and 21.6% in the fluconazole group and 64.8% in the control group after radiotherapy.

Epstein (15) reported that the rate of clinical candidiasis was 33.3% in their studies. Our control group results were similar to those in Epstein’s study (37.8%). The results for the fluconazole groups were lower than those in Epstein’s study (8.7%).

Mucke et al. (18) reported that 40% of the control patients demonstrated Candida stomatitis with 14% of them requiring interruptions of radiotherapy. None of the patients with fluconazole (100 mg/day) had evidence of Candida stomatitis and subsequent interruption of radiotherapy. Gava et al. (9) used 50 mg/day of fluconazole prophylactically in head and neck radiotherapy patients. They showed 2.5% mycotic mucositis in the prophylactic group and 63% in the control group. In both studies clinical candidiasis was lower that in our patients.

Feretti et al. (19) reported that severe, persistent xerostomia developed in patients receiving high-dose radiation therapy rather quickly (i.e. within 14–21 days) after initiation of radiation therapy, thus depriving oral epithelial tissues of their usual coating of salivary fluids and diminishing the potential mucosal protectant effect of chlorhexidine in these patients. The oral microbiology data in their study nevertheless showed reductions in total streptococci and yeast in the patients receiving radiotherapy similar to those observed in the in-patient chemotherapy group. This suggested that, although chlorhexidine mouthrinse in patients undergoing high-dose radiation therapy may not produce an antimucositis effect, it may still provide some useful oral antimicrobial activity. They suggested that this finding may be explained by the observation that the chlorhexidine molecule, a divalent cation, probably does not bind directly to epithelial tissues but rather to negatively charged salivary mucins or glycoproteins. In our patients, the time of occurrence of clinical candidiasis was generally during the third and fourth weeks of radiotherapy. Oral hygiene rules were advised to all patients. No prophylactic drug was administered except fluconazole.

These results suggest that patients undergoing head and neck radiation therapy are at risk of developing candidiasis. Fluconazole may be used to reduce the frequency of mycotic infections and to improve the radiotherapy schedule in head and neck cancer patients. Further studies are necessary to define the optimum dosage of prophylactic fluconazole.

+

For reprints and all correspondence: Mehmet Koc, Department of Radiation Oncology, Medical School, Ataturk University, 25240 Erzurum, Turkey. E-mail: mkoc@atauni.edu.tr

Table 1.

Characteristics of the study population

Characteristic Total Group A (fluconazole) Group B (control) 
Total randomized 80 40 40 
Total evaluated 74 37 37 
Gender    
 Male 61 30 31 
 Female 13 
Age: median (range) (years) 52 (19–70) 51 (19–70) 52.5 (22–70) 
Primary tumor site    
 Nasopharynx 17 
 Larynx 48 24 24 
 Hypopharynx 
 Tongue 
Concurrent chemotherapy 18 10 
Total dose of radiotherapy:    
 median (range) (cGy) 6400 (6000–6800) 6400 (6000–6800) 6400 (6000–6800) 
Dose developing candidasis:    
 median (range) (cGy) 3200 (2200–5800) 4200 (3400–5800) 2800 (2200–4400) 
Interruption of RT:    
 median (range) (days) 5 (3–7)  7(4–10) 
Characteristic Total Group A (fluconazole) Group B (control) 
Total randomized 80 40 40 
Total evaluated 74 37 37 
Gender    
 Male 61 30 31 
 Female 13 
Age: median (range) (years) 52 (19–70) 51 (19–70) 52.5 (22–70) 
Primary tumor site    
 Nasopharynx 17 
 Larynx 48 24 24 
 Hypopharynx 
 Tongue 
Concurrent chemotherapy 18 10 
Total dose of radiotherapy:    
 median (range) (cGy) 6400 (6000–6800) 6400 (6000–6800) 6400 (6000–6800) 
Dose developing candidasis:    
 median (range) (cGy) 3200 (2200–5800) 4200 (3400–5800) 2800 (2200–4400) 
Interruption of RT:    
 median (range) (days) 5 (3–7)  7(4–10) 

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Author notes

Departments of 1Radiation Oncology and 2Microbiology, Medical School, Ataturk University, Erzurum, Turkey