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A comparative study of the efficacy and safety of fluconazole oral suspension and amphotericin B oral suspension in cancer patients with mucositis
Oral Oncology 38 (2002) 337–342 www.elsevier.com/locate/oraloncology
A comparative study of the efficacy and safety of fluconazole oral suspension and amphotericin B oral suspension in cancer patients with mucositis Jean-Louis Lefebvrea,*,1, Christian Domengeb,1 a
C.R.L.C. Oscar Lambret, 1 rue Fre´de´ric Combemale, B.P. 307 59020- Lille Cedex, France b Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 - Villejuif Cedex, France
Received 26 February 2001; received in revised form 21 March 2001; accepted 23 May 2001
Abstract This randomized study compared the efficacy and safety of fluconazole suspension with that of amphotericin B suspension in patients with head and neck cancer who were suffering from candidiasis during cancer treatment with radiotherapy and/or chemotherapy. A total of 123 evaluable patients received 50 mg fluconazole once daily and 120 evaluable patients received 0.5 g amphotericin B thrice daily for 7–14 days depending on clinical response. A positive culture result was obtained in 121 of 264 (46%) patients; Candida albicans was most common. At the end of treatment, fluconazole and amphotericin B were equivalent (CI90 of 10.7 to +14.9) in terms of clinical cure and improvement, but the rate of mycologic cure was higher for fluconazole (48%) than amphotericin B (35%). The incidence of adverse events was 39% for fluconazole and 44% for amphotericin B. Fluconazole suspension appeared effective and safe. # 2002 Published by Elsevier Science Ltd. Keywords: Amphotericin B; Comparative study; Fluconazole; Head and neck neoplasms; Oral candidiasis; Suspension
1. Introduction Oropharyngeal candidiasis is a frequent infection among immunocompromised patients, and is particularly common in cancer patients [1–4]. The infection is characterized by the presence of creamy, white plaques on the tongue and buccal mucosa that generally leave a raw, painful, and ulcerated surface when scraped. Although oropharyngeal candidiasis is generally not a life-threatening infection, it can be discomforting and detrimental to the cancer patient’s nutritional status as a result of decreased food and liquid intake. In addition, spread of the initial infection to the esophagus is a common complication in the immunocompromised host. Less commonly but even more concerning in immunocompromised patients, oropharyngeal candidiasis also can ultimately lead to disseminated candidiasis. There-
* Corresponding author. Tel.: +33-3-20-29-55-31; fax: +33-3-2029-59-61. E-mail address: [email protected] (J.-L. Lefebvre). 1 On behalf of the Study Group on Mucositis.
fore, treatment of oropharyngeal candidiasis in cancer patients is imperative, even episodes that produce relatively few symptoms. A myriad of therapeutic alternatives are now available for patients with oropharyngeal candidiasis. Treatment with locally acting, topical agents such as oral nystatin and oral amphotericin B have been the mainstay of therapy for many years, due primarily to the perceived safety of these non-absorbable compounds [2]. However, poor taste acceptance and the need for multiple daily dosing compromise patient compliance with treatment regimens using these agents [4–8]. Furthermore, systemic therapy may offer a better approach than topical therapy for avoiding fungemia and other potentially life-threatening fungal infections in immunocompromised patients [2]. Fluconazole is a triazole antifungal agent that is available in both oral and parenteral formulations. An oral suspension formulation of fluconazole is available for patients who are unable to swallow a tablet or capsule. An additional benefit of the suspension formulation in treating oropharyngeal candidiasis is the potential topical effect produced by direct contact with
1368-8375/02/$ - see front matter # 2002 Published by Elsevier Science Ltd. PII: S1368-8375(01)00063-X
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the oral mucosa prior to swallowing [5,9,10]. Similar to the capsule dosage formulation, fluconazole suspension is readily absorbed from the gastrointestinal tract following oral administration. Once absorbed, fluconazole distributes extensively into body tissues and fluids, with concentrations in saliva and sputum similar to those found simultaneously in the serum [9–12]. Because of its sustained presence in saliva and extended elimination half-life of about 30 h [11,12], fluconazole maintains local activity against oropharyngeal candidiasis throughout a 24-h dosing interval. In contrast, the topical agents are rapidly cleared from the oropharyngeal mucosa with each swallow. The role of fluconazole capsules for the treatment of oropharyngeal candidiasis in patients with serious underlying diseases such as AIDS or cancer is well established, with clinical success rates in the range of 80–90% [6,13–18]. In addition, the suspension formulation of fluconazole has been shown to be effective for treating oropharyngeal or esophageal candidiasis in immunocompromised children [19], elderly patients [20], and patients with acquired immunodeficiency syndrome (AIDS) [21–23]. Fluconazole suspension has not yet been evaluated for the treatment of oropharyngeal candidiasis in adult cancer patients in a controlled clinical trial setting. Since many cancer patients, especially patients with head and neck cancer, are unable to swallow tablets or capsules as a result of their underlying disease or treatment, liquid dosage forms are preferred. This study was designed to evaluate the efficacy and safety of fluconazole suspension for the treatment of mucositis in this patient population.
2. Patients and methods This was an open-label, randomized, multicenter study comparing the efficacy and safety of fluconazole oral suspension with that of amphotericin B oral suspension in the treatment of patients with head and neck cancer who were suffering from mucositis. Male and female patients, 18 years of age or older, with head and neck cancer undergoing treatment with radiotherapy and/or chemotherapy who presented with at least one of the following signs or symptoms of mucositis were included in the study: dry mouth, burning sensation, pain, dysphagia, erythema, ulcerations, or false membranes. As part of the screening process for inclusion in the study, a sample of the oral lesions was obtained for direct microscopic examination and culture. The study was conducted in accordance with the pertinent sections of the Declaration of Helsinki and all study participants gave written informed consent before enrolling in the study. Patients who were receiving treatment with antifungal agents and/or acyclovir or who had received such treat-
ment within 3 days of enrollment in the present study were excluded. Also excluded were patients with any of the following conditions: a history of allergy to azole compounds or antifungal agents of the polyene group; abnormal liver function tests defined as a prothrombin rate of 40% or less, or AST, ALT, or total bilirubin greater than 3 times the upper limit of normal; inability to tolerate oral intake; life expectancy < 4 weeks; and pregnancy or breast feeding. Patients who required treatment with drugs likely to interact with fluconazole, specifically, vitamin K antagonists, sulfonylurea antidiabetic agents, rifampicin, phenytoin, isoniazid, or cisapride, were excluded from participation in the study. Patients who were enrolled in another investigational study, either concurrently or within the 2 weeks of the start of the current study, or who were taking any investigational medication, except for cancer chemotherapy with a well-established safety profile, were excluded. Eligible patients were randomly assigned to treatment with either fluconazole oral suspension (50 mg/5 ml; Triflucan1) once daily or amphotericin B suspension (0.5 g/5 ml) thrice daily. Since this was an open-label study, no attempt was made to blind the investigators or patients to study drug or treatment assignment. Patients randomly assigned to treatment with fluconazole were instructed to wash their mouth for 1 min with 5 ml (50 mg) of fluconazole suspension then swallow. This was to be done at the same time each day, once a day. The protocol allowed for fluconazole dosage adjustments in patients who developed renal failure. Patients randomly assigned to treatment with amphotericin B were instructed to take 5 ml (0.5 g) three times a day, preferably between meals. Patients were to be treated for a minimum of 7 days and a maximum of 14 days depending on clinical response. The study period consisted of five visits: the initial visit on Day 1, evaluation visits on Days 4, 7, and 14, and a follow-up visit 2 weeks after the end of study drug treatment. At the initial evaluation on Day 1, a physical examination (including laboratory testing) was performed and a medical history was obtained. A specimen from the oral mucosal lesions was obtained for microscopic examination (KOH preparation) and culture. Clinical assessment of mucositis included the presence of seven signs and symptoms (erythema, dysphagia, dry mouth, burning sensation, buccal pain, ulceration, and false membranes), the severity of the signs and symptoms (on a scale of 0=absent to 3=severe for each sign/ symptom; total severity score 0 to 21), and the severity of the inflammation [on a scale of grade 0 (absent) to grade IV (mucosal necrosis, parenteral nutrition required)]. The clinical assessments of inflammation were repeated on Days 4, 7, and 14, and samples of lesions were obtained by swab or smear for repeat cultures (regardless of the outcome of treatment) on Days
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7 and 14. Additional assessments conducted during the study included an evaluation of the effect of mucositis on the patient’s quality of life (oral pain, pain on eating/ drinking, and type of food/beverage ingested); the patient’s self-evaluation of treatment, examinations for signs of spread of mucositis, changes in concomitant medications, assessment of compliance with the study drug regimen, and recording of any adverse events. Any additional examinations were performed as needed, and blood samples and any other specimens were obtained from patients at the discretion of the investigators. Patients who were cured or improved after 7–14 days of study drug treatment were evaluated 2 weeks after the end of treatment. Details of any chemotherapy and/ or radiotherapy received during the 2 weeks after the end of treatment were recorded, any indication of relapse was noted, if any lesions were still present a sample was obtained, any signs and symptoms of systemic fungal infection were noted, and any non-study antifungal agents (topical or systemic) used since the end of study drug treatment were recorded. The primary efficacy parameters were the clinical and mycologic responses at the end of treatment (Day 7 or Day 14). Clinical response was defined as follows: cure (resolution of signs and symptoms of mucositis); improvement (a reduction in the number of lesions and symptoms but persistence of characteristic lesions); failure (no resolution of signs and symptoms, with persistence of or worsening of lesions). Mycologic response was defined as follows: cure (culture result negative for Candida or no lesions from which a specimen could be obtained); failure (presence of lesions with a culture result positive for Candida); colonization (positive culture result but no clinical signs or symptoms of disease). Secondary efficacy parameters included the following: relapse and signs of systemic fungal infection; change in the severity of clinical symptoms; signs of spread of infection; change in the incidence of positive or negative culture results; evaluation of treatment by the patient (practicality of treatment, taste, and ease of use), and effect of mucositis on the patient’s quality of life. Safety was based on adverse events, any changes in physical examination findings, and any changes in laboratory test results for up to 30 days after the end of study drug treatment. Equivalence between the two treatments in terms of clinical (cure, improvement, or failure) and mycologic (cure, failure, or colonization) responses was determined by calculating the confidence interval for the difference between results obtained for each treatment based on data for efficacy evaluable patients. The maximum difference allowing for the inference of equivalence between the two treatments was 20% (confidence interval of 20%). Patients evaluable for the efficacy analysis fulfilled the inclusion criteria for mucositis, were treated with study drug for a minimum of 3 days,
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received no antifungal treatment other than with study drug (except in the event of failure), and provided mucosal samples for culture before starting and at the end of treatment. Differences between the two treatments in terms of secondary efficacy variables were compared using the following statistical tests: w2 test or Fisher’s exact test for nominal qualitative variables; Wilcoxon’s test for ordinal qualitative variables; and Student’s t-test for quantitative variables.
3. Results A total of 268 patients with cancer were enrolled in the study and randomly assigned to treatment with either fluconazole oral suspension (133 patients) or amphotericin B oral suspension (135 patients). The two treatment groups were similar in terms of demographic and patient characteristics (Table 1). More than 95% of the patients had a histopathologic classification of squamous cell carcinoma. The cancer was localized in about 31% of patients and regional in 66%. At baseline, 84% of patients were receiving localized radiation therapy and 22% were receiving chemotherapy. More patients in the fluconazole group (23%) than in the amphotericin B group (10%) had abnormalities on physical examination (P=0.004). Mean red blood cell count and hemoglobin values were significantly lower (P=0.004 and P=0.02, respectively) in the fluconazole group as compared with the amphotericin B group. Of the 264 patients from whom pretreatment oropharyngeal culture specimens were obtained, 121 (46%) had a positive culture result. Candida albicans (65%) was by far the most common, followed by C. tropicalis (10%), C. kephir (9%), C. krusei (7%), and C. glabrata (6%). There was no difference between the two treatment groups in terms of the pattern or percentage of organisms identified. The mean duration of treatment was 10.5 days for fluconazole and 10.1 days for amphotericin B. Overall, 96% of patients were compliant with the study drug regimen (at least 80% of doses taken). A total of 147 patients (72 fluconazole; 75 amphotericin B) withdrew early from the study; the two treatment groups were comparable in terms of the incidence of and reasons for early withdrawal. Reasons included treatment failure (109), adverse event (13), investigator’s decision (five), patient’s decision (18), lost to follow-up (three), or other (seven). It is important to note that the patients who were prematurely withdrawn from the study due to treatment failure are included in the efficacy analyses. Ten patients in the fluconazole group and 15 in the amphotericin B group were excluded from the efficacy evaluable analysis population. Reasons for exclusion were lack of signs and symptoms of mucositis as specified by the inclusion criteria (four), < 3 days of study
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Table 1 Demographic and patient characteristics at baseline
Gender (n; %) Male Female Age (years) Mean S.D. Range Histologic classification (n; %) Squamous cell carcinoma Leiomyosarcoma Adenocarcinoma Non-Hodgkin’s lymphoma Ethmoid cancer, neuroblastoma Not specified Pathologic stage (n; %) Localized Regional Metastasized Current therapy (n; %)a Chemotherapy Radiotherapy Duration of mucositis (days) Mean S.D. Range Severity of signs and symptomsb Dry mouth Burning sensation Buccal pain Dysphagia Erythema Ulcerations False membranes Severityc of mucositis (n; %) Grade 0 Grade I Grade II Grade III Grade IV
Fluconazole (n=133)
Amphotericin B (n=135)
111 (83) 22 (17)
121 (90) 14 (10)
59 11 28–89
58 11 35–90
128 1 1 1 1 1
128 2 1 1 0 3
(96) (0.8) (0.8) (0.8) (0.8) (0.8)
(95) (1) (0.7) (0.7) (2)
42 (32) 89 (67) 2 (2)
40 (30) 89 (66) 6 (4)
32 (24) 110 (83)
26 (19) 115 (85)
11 21 <1–130
7 9 < 1–67
1.70.9 1.51.1 1.21.1 1.71.0 2.00.8 0.81.0 1.21.1
1.6 1.1 1.5 1.0 1.4 1.1 1.8 1.0 2.0 0.9 0.8 0.9 1.0 1.1
3 36 57 36 1
2 36 66 30 1
(2) (27) (43) (27) (1)
(1) (27) (49) (22) (1)
a Some patients may be counted once in each category if they received both types of therapy. b Graded on a scale of 0 (absent) to 3 (severe). For each sign or symptom, value is presented as meanS.D. c Graded on a scale of increasing severity from Grade 0 to Grade IV (mucosal necrosis, parenteral nutrition necessary).
drug treatment (11), receipt of non-study antifungal therapy (one), and no culture of an oropharyngeal specimen at pretreatment or end of treatment (13). Some patients had more than one reason for exclusion. As shown in Table 2, fluconazole and amphotericin B were equivalent (confidence interval of 10.7 to +14.9) in terms of clinical success (cure or improvement) at the end of treatment. The two treatments were not equivalent (confidence interval of 29.1 to +8.3) in terms of mycologic cure at the end of treatment (Table 2). The frequency of mycologic cure was higher for fluconazole (48%) than for amphotericin B (35%).
There were no statistically significant differences between fluconazole and amphotericin B in terms of the secondary efficacy variables with the exception of signs of spread of mucositis and change in mycologic evaluation. The incidence of relapse of mucositis was 26% in the fluconazole group as compared with 30% in the amphotericin B group. No patients exhibited signs of systemic fungal infection during the study. The changes in clinical signs/symptoms were globally comparable between the two treatment groups. The total severity score (sum of the individual scores for each of the seven signs/symptoms) decreased slightly from Day 1 (10.2 and 10.3 for fluconazole and amphotericin B, respectively) to Day 7 (8.9 for both treatment groups), with marked decreases at Day 14 (6.4 and 5.7, respectively) and the post-treatment follow-up visit (4.5 and 5.1, respectively), indicating improvement. The percentage of patients with signs of spread of mucositis at Day 7 was higher (P=0.03) in the fluconazole group (39%, 18/46) than in the amphotericin B group (19%, 9/47). The percentage of patients with a positive culture result on Day 7 was higher (P=0.02) in the amphotericin B group (38%, 42/ 112) than in the fluconazole group (24%, 28/119). At subsequent visits, there was no significant difference between the two treatment groups with regard to signs of spread or change in mycologic results. Among patients who provided their assessment of study drug treatment, more fluconazole-treated (58%, 71/122) than amphotericin B-treated patients (37%, 43/ 117) considered their treatment to be practical (P=0.0007). More patients treated with fluconazole (76%, 92/121) than amphotericin B (46%, 54/117) thought the suspension tasted pleasant or very pleasant (P=0.0001). There was no statistically significant difference between the two treatment groups in terms of ease of use of the drug. Eleven patients in the fluconazole group and six in the amphotericin B group received an antifungal agent after discontinuation of study drug treatment. The two treatment groups were comparable in terms of the incidence of patients with adverse events and the incidence of patients withdrawn from the study due to adverse events (Table 3). The most common adverse event was nausea, reported for 10% of fluconazole-treated and 8% of amphotericin B-treated patients. All other adverse events occurred with an incidence of 4% or less. None of the patient deaths was considered by the investigators to be related to study drug treatment. Hematology and blood chemistry values generally remained stable at Days 7 and 14 in both treatment groups.
4. Discussion The results of this comparative, randomized, multicenter study demonstrated that fluconazole oral
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Clinical responsea Cureb Improvementb Failure Not determined Mycologic responsea,c Cured Failure Colonization Not determined
Fluconazole
Amphotericin B
(n=123) 26 (21) 39 (32) 57 (46) 1 (1) (n=52) 25 (48) 19 (37) 7 (13) 1 (2)
(n=120) 17 (14) 45 (38) 50 (42) 8 (7) (n=63) 22 (35) 33 (52) 2 (3) 6 (10)
a
Presented as number of patients (%). Confidence interval for clinical cure plus improvement: 10.7 to +14.9. c The end-of-treatment mycologic evaluation was performed only in patients who had a positive Candida culture result at baseline (52 in the fluconazole group and 63 in the amphotericin B group). d Confidence interval for mycologic cure: 29.1 to +8.3. b
suspension 50 mg once daily and amphotericin B suspension 0.5 g thrice daily were equivalent in producing clinical success (cure or improvement) in cancer patients with candidal mucositis. In terms of eradication of Candida, however, fluconazole suspension produced a higher cure rate as compared with amphotericin B suspension. The clinical success and mycologic cure rates in cancer patients with mucositis observed in this study are consistent with results from previous controlled clinical investigations that evaluated fluconazole suspension in treating oropharyngeal candidiasis in immunocompromised children [19], elderly patients [20], and patients with AIDS [21,23]. In these previous studies, fluconazole suspension (50–100 mg/day in adults and 2–3 mg/ kg/day in children) produced significantly higher clinical cure rates as compared with nystatin suspension [19,23], and similar clinical cure rates as compared with amphotericin B suspension [20]. In addition to producing higher mycologic cure rates, fluconazole suspension was also better accepted by patients as therapy for mucositis than was amphotericin B. A significantly higher percentage of patients rated treatment with the fluconazole suspension as practical to use, most likely due to its once-daily regimen as compared with the required three daily doses for amphotericin B suspension. In addition, 76% of fluconazole-treated patients found the taste of the suspension formulation to be acceptable compared with 46% of amphotericin B-treated patients (P=0.0001). Rapidity of response is an important consideration in the management of oropharyngeal candidiasis in cancer patients. Indeed, a rapid response to treatment has been observed in patients with oropharyngeal candidiasis treated with fluconazole, even in those with complicated infections [8,14]. The rapid resolution of symptoms with
Table 3 Adverse events Adverse event
Fluconazole (n=133)
Amphotericin B (n=135)
Nausea Epidermal inflammation Weight loss Constipation Death Diarrhea Epithelitis Deterioration in general condition Asthenia Dysphagia Erythema At least one adverse event Withdrawal due to adverse event
13 3 5 4 5 4 1 3 1 2 1 52 5
11 6 3 3 2 2 5 2 4 3 4 60 8
(10) (2) (4) (3) (4) (3) (1) (2) (1) (2) (1) (39) (4)
(8) (4) (2) (2) (1) (1) (4) (1) (3) (2) (3) (44) (6)
fluconazole suspension found in this study (marked decreases in symptom scores by Day 14) is consistent with previous findings. In a controlled study in elderly patients with oropharyngeal candidiasis [20], the bothersome clinical symptoms of burning sensation and buccal pain responded more quickly to fluconazole suspension as compared with amphotericin B suspension. In an uncontrolled study evaluating the use of fluconazole suspension to treat esophageal candidiasis in patients with AIDS, symptoms resolved in 41% of patients within 1 week and 90% of patients within 2 weeks [21]. Fluconazole suspension was well tolerated in this population of cancer patients. Even though fluconazole is well absorbed following oral administration of the suspension—in contrast to the poor oral bioavailability with amphotericin B suspension—analysis of safety results revealed no clinically relevant differences between treatment groups. Both fluconazole and amphotericin B oral suspension were well tolerated. Most of the adverse effects reported in the fluconazole and amphotericin B groups were gastrointestinal in nature, and few patients discontinued treatment because of adverse effects. In summary, the combined efficacy, safety, and patient preference results from this study indicate that fluconazole suspension is a useful therapeutic alternative for treating mucositis in cancer patients. The suspension formulation is particularly well suited for patients who are unable to swallow the capsule dosage form, including young children, patients with a nasogastric tube in place, or patients with difficulty in swallowing due to oropharyngeal mucositis.
Acknowledgements This work was supported by a grant from Pfizer France. The authors wish to express their thanks to Dr. Yong-Un Esnault for her technical assistance.
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Study group on Mucositis: Dr. J.L. Labourey, Centre Hospitalier Antoine Gayraud, Carcassonne; Dr. J.P. Rame, Centre Francois Balesse, Caen; Dr. Rives and Professor Daly, Centre Claudius Regaud, Toulouse; Professor J.B. Dubois, Centre Paul Lamarque, Montpellier; Dr. O. Laecourreye, Hoˆpital Laennec, Paris; Professor G. Calais, Hoˆpital Bretonneau, Tours; Dr. A. Perrin, Centre Hospitalier, Le Mans; Professor T.D. Nguyen, Institut Jean Godinot, Reims; Dr. G.M. Jung, Centre Paul Strauss, Strasbourg; Professor A. Daban, Hoˆpital Jean Bernard, Poitiers; Dr. J.Y. Ranchere, Centre Le´on Be´rard, Lyon; Professor M. Bolla, CHU Michalon, Grenoble; Dr. T. Pignon, Centre Paoli Calmette, Marseille; Dr. F. Bons-Rosset, Hoˆpital Care´meau, Nimes; Dr. J.M. Prades, Hoˆpital Bellevue, Saint Etienne; Dr. P. Maingon, Centre Georges Franc¸ois Leclerc, Dijon; Dr. J.L. Floiras, Centre Rene´ Huguenin, Saint Cloud; Dr. E. Haddad, Hoˆpital Henri Mondor, Creteil; Dr. O. Esnault, Hoˆpital Saint Louis, Paris; Professor Baillet, CH Pitie´ Salpe´trie`re, Paris; Dr. M. Martin, CHI Cre´teil, Cre´teil; Professor J.P. Labat, CHU Morvan, Brest; Dr. P. Ayela, Clinique de l’Ormeau, Tarbes; Dr. Delpon, Centre Jean Bernard, Le Mans.
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A comparative study of the efficacy and safety of fluconazole oral suspension and amphotericin B oral suspension in cancer patients with mucositis Jean-Louis Lefebvrea,*,1, Christian Domengeb,1 a
C.R.L.C. Oscar Lambret, 1 rue Fre´de´ric Combemale, B.P. 307 59020- Lille Cedex, France b Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 - Villejuif Cedex, France
Received 26 February 2001; received in revised form 21 March 2001; accepted 23 May 2001
Abstract This randomized study compared the efficacy and safety of fluconazole suspension with that of amphotericin B suspension in patients with head and neck cancer who were suffering from candidiasis during cancer treatment with radiotherapy and/or chemotherapy. A total of 123 evaluable patients received 50 mg fluconazole once daily and 120 evaluable patients received 0.5 g amphotericin B thrice daily for 7–14 days depending on clinical response. A positive culture result was obtained in 121 of 264 (46%) patients; Candida albicans was most common. At the end of treatment, fluconazole and amphotericin B were equivalent (CI90 of 10.7 to +14.9) in terms of clinical cure and improvement, but the rate of mycologic cure was higher for fluconazole (48%) than amphotericin B (35%). The incidence of adverse events was 39% for fluconazole and 44% for amphotericin B. Fluconazole suspension appeared effective and safe. # 2002 Published by Elsevier Science Ltd. Keywords: Amphotericin B; Comparative study; Fluconazole; Head and neck neoplasms; Oral candidiasis; Suspension
1. Introduction Oropharyngeal candidiasis is a frequent infection among immunocompromised patients, and is particularly common in cancer patients [1–4]. The infection is characterized by the presence of creamy, white plaques on the tongue and buccal mucosa that generally leave a raw, painful, and ulcerated surface when scraped. Although oropharyngeal candidiasis is generally not a life-threatening infection, it can be discomforting and detrimental to the cancer patient’s nutritional status as a result of decreased food and liquid intake. In addition, spread of the initial infection to the esophagus is a common complication in the immunocompromised host. Less commonly but even more concerning in immunocompromised patients, oropharyngeal candidiasis also can ultimately lead to disseminated candidiasis. There-
* Corresponding author. Tel.: +33-3-20-29-55-31; fax: +33-3-2029-59-61. E-mail address: [email protected] (J.-L. Lefebvre). 1 On behalf of the Study Group on Mucositis.
fore, treatment of oropharyngeal candidiasis in cancer patients is imperative, even episodes that produce relatively few symptoms. A myriad of therapeutic alternatives are now available for patients with oropharyngeal candidiasis. Treatment with locally acting, topical agents such as oral nystatin and oral amphotericin B have been the mainstay of therapy for many years, due primarily to the perceived safety of these non-absorbable compounds [2]. However, poor taste acceptance and the need for multiple daily dosing compromise patient compliance with treatment regimens using these agents [4–8]. Furthermore, systemic therapy may offer a better approach than topical therapy for avoiding fungemia and other potentially life-threatening fungal infections in immunocompromised patients [2]. Fluconazole is a triazole antifungal agent that is available in both oral and parenteral formulations. An oral suspension formulation of fluconazole is available for patients who are unable to swallow a tablet or capsule. An additional benefit of the suspension formulation in treating oropharyngeal candidiasis is the potential topical effect produced by direct contact with
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the oral mucosa prior to swallowing [5,9,10]. Similar to the capsule dosage formulation, fluconazole suspension is readily absorbed from the gastrointestinal tract following oral administration. Once absorbed, fluconazole distributes extensively into body tissues and fluids, with concentrations in saliva and sputum similar to those found simultaneously in the serum [9–12]. Because of its sustained presence in saliva and extended elimination half-life of about 30 h [11,12], fluconazole maintains local activity against oropharyngeal candidiasis throughout a 24-h dosing interval. In contrast, the topical agents are rapidly cleared from the oropharyngeal mucosa with each swallow. The role of fluconazole capsules for the treatment of oropharyngeal candidiasis in patients with serious underlying diseases such as AIDS or cancer is well established, with clinical success rates in the range of 80–90% [6,13–18]. In addition, the suspension formulation of fluconazole has been shown to be effective for treating oropharyngeal or esophageal candidiasis in immunocompromised children [19], elderly patients [20], and patients with acquired immunodeficiency syndrome (AIDS) [21–23]. Fluconazole suspension has not yet been evaluated for the treatment of oropharyngeal candidiasis in adult cancer patients in a controlled clinical trial setting. Since many cancer patients, especially patients with head and neck cancer, are unable to swallow tablets or capsules as a result of their underlying disease or treatment, liquid dosage forms are preferred. This study was designed to evaluate the efficacy and safety of fluconazole suspension for the treatment of mucositis in this patient population.
2. Patients and methods This was an open-label, randomized, multicenter study comparing the efficacy and safety of fluconazole oral suspension with that of amphotericin B oral suspension in the treatment of patients with head and neck cancer who were suffering from mucositis. Male and female patients, 18 years of age or older, with head and neck cancer undergoing treatment with radiotherapy and/or chemotherapy who presented with at least one of the following signs or symptoms of mucositis were included in the study: dry mouth, burning sensation, pain, dysphagia, erythema, ulcerations, or false membranes. As part of the screening process for inclusion in the study, a sample of the oral lesions was obtained for direct microscopic examination and culture. The study was conducted in accordance with the pertinent sections of the Declaration of Helsinki and all study participants gave written informed consent before enrolling in the study. Patients who were receiving treatment with antifungal agents and/or acyclovir or who had received such treat-
ment within 3 days of enrollment in the present study were excluded. Also excluded were patients with any of the following conditions: a history of allergy to azole compounds or antifungal agents of the polyene group; abnormal liver function tests defined as a prothrombin rate of 40% or less, or AST, ALT, or total bilirubin greater than 3 times the upper limit of normal; inability to tolerate oral intake; life expectancy < 4 weeks; and pregnancy or breast feeding. Patients who required treatment with drugs likely to interact with fluconazole, specifically, vitamin K antagonists, sulfonylurea antidiabetic agents, rifampicin, phenytoin, isoniazid, or cisapride, were excluded from participation in the study. Patients who were enrolled in another investigational study, either concurrently or within the 2 weeks of the start of the current study, or who were taking any investigational medication, except for cancer chemotherapy with a well-established safety profile, were excluded. Eligible patients were randomly assigned to treatment with either fluconazole oral suspension (50 mg/5 ml; Triflucan1) once daily or amphotericin B suspension (0.5 g/5 ml) thrice daily. Since this was an open-label study, no attempt was made to blind the investigators or patients to study drug or treatment assignment. Patients randomly assigned to treatment with fluconazole were instructed to wash their mouth for 1 min with 5 ml (50 mg) of fluconazole suspension then swallow. This was to be done at the same time each day, once a day. The protocol allowed for fluconazole dosage adjustments in patients who developed renal failure. Patients randomly assigned to treatment with amphotericin B were instructed to take 5 ml (0.5 g) three times a day, preferably between meals. Patients were to be treated for a minimum of 7 days and a maximum of 14 days depending on clinical response. The study period consisted of five visits: the initial visit on Day 1, evaluation visits on Days 4, 7, and 14, and a follow-up visit 2 weeks after the end of study drug treatment. At the initial evaluation on Day 1, a physical examination (including laboratory testing) was performed and a medical history was obtained. A specimen from the oral mucosal lesions was obtained for microscopic examination (KOH preparation) and culture. Clinical assessment of mucositis included the presence of seven signs and symptoms (erythema, dysphagia, dry mouth, burning sensation, buccal pain, ulceration, and false membranes), the severity of the signs and symptoms (on a scale of 0=absent to 3=severe for each sign/ symptom; total severity score 0 to 21), and the severity of the inflammation [on a scale of grade 0 (absent) to grade IV (mucosal necrosis, parenteral nutrition required)]. The clinical assessments of inflammation were repeated on Days 4, 7, and 14, and samples of lesions were obtained by swab or smear for repeat cultures (regardless of the outcome of treatment) on Days
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7 and 14. Additional assessments conducted during the study included an evaluation of the effect of mucositis on the patient’s quality of life (oral pain, pain on eating/ drinking, and type of food/beverage ingested); the patient’s self-evaluation of treatment, examinations for signs of spread of mucositis, changes in concomitant medications, assessment of compliance with the study drug regimen, and recording of any adverse events. Any additional examinations were performed as needed, and blood samples and any other specimens were obtained from patients at the discretion of the investigators. Patients who were cured or improved after 7–14 days of study drug treatment were evaluated 2 weeks after the end of treatment. Details of any chemotherapy and/ or radiotherapy received during the 2 weeks after the end of treatment were recorded, any indication of relapse was noted, if any lesions were still present a sample was obtained, any signs and symptoms of systemic fungal infection were noted, and any non-study antifungal agents (topical or systemic) used since the end of study drug treatment were recorded. The primary efficacy parameters were the clinical and mycologic responses at the end of treatment (Day 7 or Day 14). Clinical response was defined as follows: cure (resolution of signs and symptoms of mucositis); improvement (a reduction in the number of lesions and symptoms but persistence of characteristic lesions); failure (no resolution of signs and symptoms, with persistence of or worsening of lesions). Mycologic response was defined as follows: cure (culture result negative for Candida or no lesions from which a specimen could be obtained); failure (presence of lesions with a culture result positive for Candida); colonization (positive culture result but no clinical signs or symptoms of disease). Secondary efficacy parameters included the following: relapse and signs of systemic fungal infection; change in the severity of clinical symptoms; signs of spread of infection; change in the incidence of positive or negative culture results; evaluation of treatment by the patient (practicality of treatment, taste, and ease of use), and effect of mucositis on the patient’s quality of life. Safety was based on adverse events, any changes in physical examination findings, and any changes in laboratory test results for up to 30 days after the end of study drug treatment. Equivalence between the two treatments in terms of clinical (cure, improvement, or failure) and mycologic (cure, failure, or colonization) responses was determined by calculating the confidence interval for the difference between results obtained for each treatment based on data for efficacy evaluable patients. The maximum difference allowing for the inference of equivalence between the two treatments was 20% (confidence interval of 20%). Patients evaluable for the efficacy analysis fulfilled the inclusion criteria for mucositis, were treated with study drug for a minimum of 3 days,
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received no antifungal treatment other than with study drug (except in the event of failure), and provided mucosal samples for culture before starting and at the end of treatment. Differences between the two treatments in terms of secondary efficacy variables were compared using the following statistical tests: w2 test or Fisher’s exact test for nominal qualitative variables; Wilcoxon’s test for ordinal qualitative variables; and Student’s t-test for quantitative variables.
3. Results A total of 268 patients with cancer were enrolled in the study and randomly assigned to treatment with either fluconazole oral suspension (133 patients) or amphotericin B oral suspension (135 patients). The two treatment groups were similar in terms of demographic and patient characteristics (Table 1). More than 95% of the patients had a histopathologic classification of squamous cell carcinoma. The cancer was localized in about 31% of patients and regional in 66%. At baseline, 84% of patients were receiving localized radiation therapy and 22% were receiving chemotherapy. More patients in the fluconazole group (23%) than in the amphotericin B group (10%) had abnormalities on physical examination (P=0.004). Mean red blood cell count and hemoglobin values were significantly lower (P=0.004 and P=0.02, respectively) in the fluconazole group as compared with the amphotericin B group. Of the 264 patients from whom pretreatment oropharyngeal culture specimens were obtained, 121 (46%) had a positive culture result. Candida albicans (65%) was by far the most common, followed by C. tropicalis (10%), C. kephir (9%), C. krusei (7%), and C. glabrata (6%). There was no difference between the two treatment groups in terms of the pattern or percentage of organisms identified. The mean duration of treatment was 10.5 days for fluconazole and 10.1 days for amphotericin B. Overall, 96% of patients were compliant with the study drug regimen (at least 80% of doses taken). A total of 147 patients (72 fluconazole; 75 amphotericin B) withdrew early from the study; the two treatment groups were comparable in terms of the incidence of and reasons for early withdrawal. Reasons included treatment failure (109), adverse event (13), investigator’s decision (five), patient’s decision (18), lost to follow-up (three), or other (seven). It is important to note that the patients who were prematurely withdrawn from the study due to treatment failure are included in the efficacy analyses. Ten patients in the fluconazole group and 15 in the amphotericin B group were excluded from the efficacy evaluable analysis population. Reasons for exclusion were lack of signs and symptoms of mucositis as specified by the inclusion criteria (four), < 3 days of study
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Table 1 Demographic and patient characteristics at baseline
Gender (n; %) Male Female Age (years) Mean S.D. Range Histologic classification (n; %) Squamous cell carcinoma Leiomyosarcoma Adenocarcinoma Non-Hodgkin’s lymphoma Ethmoid cancer, neuroblastoma Not specified Pathologic stage (n; %) Localized Regional Metastasized Current therapy (n; %)a Chemotherapy Radiotherapy Duration of mucositis (days) Mean S.D. Range Severity of signs and symptomsb Dry mouth Burning sensation Buccal pain Dysphagia Erythema Ulcerations False membranes Severityc of mucositis (n; %) Grade 0 Grade I Grade II Grade III Grade IV
Fluconazole (n=133)
Amphotericin B (n=135)
111 (83) 22 (17)
121 (90) 14 (10)
59 11 28–89
58 11 35–90
128 1 1 1 1 1
128 2 1 1 0 3
(96) (0.8) (0.8) (0.8) (0.8) (0.8)
(95) (1) (0.7) (0.7) (2)
42 (32) 89 (67) 2 (2)
40 (30) 89 (66) 6 (4)
32 (24) 110 (83)
26 (19) 115 (85)
11 21 <1–130
7 9 < 1–67
1.70.9 1.51.1 1.21.1 1.71.0 2.00.8 0.81.0 1.21.1
1.6 1.1 1.5 1.0 1.4 1.1 1.8 1.0 2.0 0.9 0.8 0.9 1.0 1.1
3 36 57 36 1
2 36 66 30 1
(2) (27) (43) (27) (1)
(1) (27) (49) (22) (1)
a Some patients may be counted once in each category if they received both types of therapy. b Graded on a scale of 0 (absent) to 3 (severe). For each sign or symptom, value is presented as meanS.D. c Graded on a scale of increasing severity from Grade 0 to Grade IV (mucosal necrosis, parenteral nutrition necessary).
drug treatment (11), receipt of non-study antifungal therapy (one), and no culture of an oropharyngeal specimen at pretreatment or end of treatment (13). Some patients had more than one reason for exclusion. As shown in Table 2, fluconazole and amphotericin B were equivalent (confidence interval of 10.7 to +14.9) in terms of clinical success (cure or improvement) at the end of treatment. The two treatments were not equivalent (confidence interval of 29.1 to +8.3) in terms of mycologic cure at the end of treatment (Table 2). The frequency of mycologic cure was higher for fluconazole (48%) than for amphotericin B (35%).
There were no statistically significant differences between fluconazole and amphotericin B in terms of the secondary efficacy variables with the exception of signs of spread of mucositis and change in mycologic evaluation. The incidence of relapse of mucositis was 26% in the fluconazole group as compared with 30% in the amphotericin B group. No patients exhibited signs of systemic fungal infection during the study. The changes in clinical signs/symptoms were globally comparable between the two treatment groups. The total severity score (sum of the individual scores for each of the seven signs/symptoms) decreased slightly from Day 1 (10.2 and 10.3 for fluconazole and amphotericin B, respectively) to Day 7 (8.9 for both treatment groups), with marked decreases at Day 14 (6.4 and 5.7, respectively) and the post-treatment follow-up visit (4.5 and 5.1, respectively), indicating improvement. The percentage of patients with signs of spread of mucositis at Day 7 was higher (P=0.03) in the fluconazole group (39%, 18/46) than in the amphotericin B group (19%, 9/47). The percentage of patients with a positive culture result on Day 7 was higher (P=0.02) in the amphotericin B group (38%, 42/ 112) than in the fluconazole group (24%, 28/119). At subsequent visits, there was no significant difference between the two treatment groups with regard to signs of spread or change in mycologic results. Among patients who provided their assessment of study drug treatment, more fluconazole-treated (58%, 71/122) than amphotericin B-treated patients (37%, 43/ 117) considered their treatment to be practical (P=0.0007). More patients treated with fluconazole (76%, 92/121) than amphotericin B (46%, 54/117) thought the suspension tasted pleasant or very pleasant (P=0.0001). There was no statistically significant difference between the two treatment groups in terms of ease of use of the drug. Eleven patients in the fluconazole group and six in the amphotericin B group received an antifungal agent after discontinuation of study drug treatment. The two treatment groups were comparable in terms of the incidence of patients with adverse events and the incidence of patients withdrawn from the study due to adverse events (Table 3). The most common adverse event was nausea, reported for 10% of fluconazole-treated and 8% of amphotericin B-treated patients. All other adverse events occurred with an incidence of 4% or less. None of the patient deaths was considered by the investigators to be related to study drug treatment. Hematology and blood chemistry values generally remained stable at Days 7 and 14 in both treatment groups.
4. Discussion The results of this comparative, randomized, multicenter study demonstrated that fluconazole oral
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Clinical responsea Cureb Improvementb Failure Not determined Mycologic responsea,c Cured Failure Colonization Not determined
Fluconazole
Amphotericin B
(n=123) 26 (21) 39 (32) 57 (46) 1 (1) (n=52) 25 (48) 19 (37) 7 (13) 1 (2)
(n=120) 17 (14) 45 (38) 50 (42) 8 (7) (n=63) 22 (35) 33 (52) 2 (3) 6 (10)
a
Presented as number of patients (%). Confidence interval for clinical cure plus improvement: 10.7 to +14.9. c The end-of-treatment mycologic evaluation was performed only in patients who had a positive Candida culture result at baseline (52 in the fluconazole group and 63 in the amphotericin B group). d Confidence interval for mycologic cure: 29.1 to +8.3. b
suspension 50 mg once daily and amphotericin B suspension 0.5 g thrice daily were equivalent in producing clinical success (cure or improvement) in cancer patients with candidal mucositis. In terms of eradication of Candida, however, fluconazole suspension produced a higher cure rate as compared with amphotericin B suspension. The clinical success and mycologic cure rates in cancer patients with mucositis observed in this study are consistent with results from previous controlled clinical investigations that evaluated fluconazole suspension in treating oropharyngeal candidiasis in immunocompromised children [19], elderly patients [20], and patients with AIDS [21,23]. In these previous studies, fluconazole suspension (50–100 mg/day in adults and 2–3 mg/ kg/day in children) produced significantly higher clinical cure rates as compared with nystatin suspension [19,23], and similar clinical cure rates as compared with amphotericin B suspension [20]. In addition to producing higher mycologic cure rates, fluconazole suspension was also better accepted by patients as therapy for mucositis than was amphotericin B. A significantly higher percentage of patients rated treatment with the fluconazole suspension as practical to use, most likely due to its once-daily regimen as compared with the required three daily doses for amphotericin B suspension. In addition, 76% of fluconazole-treated patients found the taste of the suspension formulation to be acceptable compared with 46% of amphotericin B-treated patients (P=0.0001). Rapidity of response is an important consideration in the management of oropharyngeal candidiasis in cancer patients. Indeed, a rapid response to treatment has been observed in patients with oropharyngeal candidiasis treated with fluconazole, even in those with complicated infections [8,14]. The rapid resolution of symptoms with
Table 3 Adverse events Adverse event
Fluconazole (n=133)
Amphotericin B (n=135)
Nausea Epidermal inflammation Weight loss Constipation Death Diarrhea Epithelitis Deterioration in general condition Asthenia Dysphagia Erythema At least one adverse event Withdrawal due to adverse event
13 3 5 4 5 4 1 3 1 2 1 52 5
11 6 3 3 2 2 5 2 4 3 4 60 8
(10) (2) (4) (3) (4) (3) (1) (2) (1) (2) (1) (39) (4)
(8) (4) (2) (2) (1) (1) (4) (1) (3) (2) (3) (44) (6)
fluconazole suspension found in this study (marked decreases in symptom scores by Day 14) is consistent with previous findings. In a controlled study in elderly patients with oropharyngeal candidiasis [20], the bothersome clinical symptoms of burning sensation and buccal pain responded more quickly to fluconazole suspension as compared with amphotericin B suspension. In an uncontrolled study evaluating the use of fluconazole suspension to treat esophageal candidiasis in patients with AIDS, symptoms resolved in 41% of patients within 1 week and 90% of patients within 2 weeks [21]. Fluconazole suspension was well tolerated in this population of cancer patients. Even though fluconazole is well absorbed following oral administration of the suspension—in contrast to the poor oral bioavailability with amphotericin B suspension—analysis of safety results revealed no clinically relevant differences between treatment groups. Both fluconazole and amphotericin B oral suspension were well tolerated. Most of the adverse effects reported in the fluconazole and amphotericin B groups were gastrointestinal in nature, and few patients discontinued treatment because of adverse effects. In summary, the combined efficacy, safety, and patient preference results from this study indicate that fluconazole suspension is a useful therapeutic alternative for treating mucositis in cancer patients. The suspension formulation is particularly well suited for patients who are unable to swallow the capsule dosage form, including young children, patients with a nasogastric tube in place, or patients with difficulty in swallowing due to oropharyngeal mucositis.
Acknowledgements This work was supported by a grant from Pfizer France. The authors wish to express their thanks to Dr. Yong-Un Esnault for her technical assistance.
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Study group on Mucositis: Dr. J.L. Labourey, Centre Hospitalier Antoine Gayraud, Carcassonne; Dr. J.P. Rame, Centre Francois Balesse, Caen; Dr. Rives and Professor Daly, Centre Claudius Regaud, Toulouse; Professor J.B. Dubois, Centre Paul Lamarque, Montpellier; Dr. O. Laecourreye, Hoˆpital Laennec, Paris; Professor G. Calais, Hoˆpital Bretonneau, Tours; Dr. A. Perrin, Centre Hospitalier, Le Mans; Professor T.D. Nguyen, Institut Jean Godinot, Reims; Dr. G.M. Jung, Centre Paul Strauss, Strasbourg; Professor A. Daban, Hoˆpital Jean Bernard, Poitiers; Dr. J.Y. Ranchere, Centre Le´on Be´rard, Lyon; Professor M. Bolla, CHU Michalon, Grenoble; Dr. T. Pignon, Centre Paoli Calmette, Marseille; Dr. F. Bons-Rosset, Hoˆpital Care´meau, Nimes; Dr. J.M. Prades, Hoˆpital Bellevue, Saint Etienne; Dr. P. Maingon, Centre Georges Franc¸ois Leclerc, Dijon; Dr. J.L. Floiras, Centre Rene´ Huguenin, Saint Cloud; Dr. E. Haddad, Hoˆpital Henri Mondor, Creteil; Dr. O. Esnault, Hoˆpital Saint Louis, Paris; Professor Baillet, CH Pitie´ Salpe´trie`re, Paris; Dr. M. Martin, CHI Cre´teil, Cre´teil; Professor J.P. Labat, CHU Morvan, Brest; Dr. P. Ayela, Clinique de l’Ormeau, Tarbes; Dr. Delpon, Centre Jean Bernard, Le Mans.
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