Topical imiquimod 5% cream and 5-fluorouracil 0.5% microsphere cream are used for treatment of actinic keratosis. Yet to date, no blinded trials have directly compared the severity of symptoms associated with these two agents. Visible inflammation in the region of application is common during treatment with either of these therapies, although some literature has suggested that the severity of symptomatology (eg burning, stinging, pain) differs between the two agents.
This article reports on application-site tolerability results from an investigator-blinded, 4-week, randomized, bilateral comparison trial of imiquimod 5% cream (Aldara) applied 3 times per week (n=30) and 5-fluorouracil 0.5% cream (Carac) applied once daily (n=30) to the forehead region, cheeks or dorsum of the hands of adult patients with actinic keratosis. Patients were assessed weekly over 4 weeks using a four-point scale (none, mild, moderate, severe) to individually evaluate visible signs of inflammation, including erythema, erosion, crusting and edema. Participants used a daily subject diary to individually assess signs (such as erythema, oozing, scabbing) and symptoms (including burning, stinging, pruritus, pain), and patients reported on their preferred treatment.
Background
Topical imiquimod 5% cream and topical 5-fluorouracil (5-FU) 0.5% cream, formulated in a porous microsphere vehicle, are both approved by the FDA for treating actinic keratosis (AK) based on proven efficacy and safety in Phase III pivotal trials.1,2
Recommended use of topical 5-FU 0.5% for AK is once daily for up to 4 weeks, with continued treatment up to 4 weeks reported to result in greater lesion reduction.2
The approved treatment regimen for use of topical imiquimod for AK is application two times per week for 16 weeks, although several other regimens have been recommended in the literature.3 Cycle therapy with topical imiquimod has been suggested as a practical method of use for AK.3,4 A single cycle of imiquimod is application three times per week for 4 weeks followed by 4 weeks off of therapy (“4 weeks on, 4 weeks off”). In one study, a single cycle of treatment, which is essentially 4 weeks of active therapy followed by a 4-week rest period, produced complete clearance of 46% of treated cosmetic units.
Therapy with topical imiquimod or 5-FU 0.5% cream characteristically produces varying degrees of visible inflammation characterized by erythema, crusting and in some cases erosion.1-5 Associated symptoms may include stinging, burning and pruritus.
One split-face, single-blind, randomized trial reported greater tolerability with the 5-FU 0.5% as compared to 5-FU 5% cream for treatment of AK.5
There has been some suggestion based on clinical observation that despite the presence of visible inflammation with both therapies for AK, symptomatology is usually less severe with topical imiquimod as compared to topical 5-FU therapy.6 Well-designed controlled studies are needed to further evaluate this clinical observation.
Mechanisms of Action
Despite the presence of visible inflammation observed after use of either agent, it is important to recognize that 5-fluorouracil and imiquimod work through different mechanisms of action.
5-fluorouracil is a chemotherapeutic agent that produces direct cytotoxicity preferentially affecting more actively dividing cells, thus inducing an inflammatory reaction.
Imiquimod facilitates and augments both innate and acquired immune responses with production of multiple cytokines and infiltration of predominantly lymphocytes within the region of application which are directed against the treated disease (ie. AK). Therefore, the visible inflammation occurring in association with imiquimod application reflects an inflammatory response.
The following discusses tolerability results from the aforementioned investigator-blinded, side-to-side comparison of imiquimod 5% cream applied three times weekly for 4 weeks and 5-FU 0.5% cream applied daily for 4 weeks. Investigator and patient assessments were completed during the study.
REVIEWING THE STUDY SPECIFICS
Inclusion Criteria
• Male or female adult patients
• Symmetric involvement with AK of forehead, cheeks and dorsal hands (affected forearms also included if symmetric involvement was present) Symmetry was defined as a minimum of eight AKs in each treatment area (+/- two AK difference between treated sides) at baseline.
• Affirmation of informed consent from patients.
Exclusion Criteria
• Use of topical therapy for AK other than sunscreen protection within 6 months of baseline evaluation.
• Use of topical corticosteroids on affected areas within 30 days of baseline evaluation and throughout trial.
• Use of any systemic immunosuppressive or anti-inflammatory therapy within 30 days of baseline evaluation and throughout trial.
• History of previous treatment with topical imiquimod or topical 5-FU.
• A clinically significant skin condition that was determined by the investigator to interfere with study evaluation or participation.
• Pregnant or nursing female patients.
Study Design
• Investigator-blinded, bilateral comparative 4-week trial.
• Symmetric involvement with AK on the forehead, cheeks or dorsal hands (forearms included if symmetrically involved.
• Treatment sides randomized.
Subject Disposition
• 30 adult Caucasian patients; 19 males, 11 females; mean age 58 years (range 44 to 71 years); all 30 patients completed the trial.
• Symmetric involvement with AK of forehead (including temple region), cheeks or dorsal hands (forearms included if symmetrically involved).
• Treatment sides were randomized and maintained consistently throughout the study. Only a single designated anatomic area on each side was treated per patient.
• Treatment areas included forehead (n=7), cheeks (n=4), dorsal hands with forearms (n=12) and dorsal hands without forearms (n=7).
• Treatments were as follows:
• Imiquimod 5% cream applied three times per week x 4 weeks to one side.
• Fluorouracil 0.5% cream applied once daily x 4 weeks to opposite side.
Assessments
• Patients evaluated at baseline, week 1, week 2, week 3 and week 4. Parameters evaluated and graded included erythema, edema, crusting and erosion (see Table 1).
• Patients instructed to maintain daily log and grading of each of the following parameters: visible redness, scabbing, oozing (exudation), stinging, burning, pain, itching.
• At study endpoint, patients were asked to indicate which treatment they preferred and if they would repeat therapy with either agent in the future.
Results
The results of the trial are tabulated in Tables 3 through 6.
Patient Preference. When queried regarding preference, 15 patients preferred imiquimod, 8 patients preferred 5-FU 0.5%, and 7 patients stated no preference. With regard to use in the future if a treatment for AK is needed, 27 patients stated they would be willing to use imiquimod and 21 patients stated they would be willing to use 5-FU 0.5%.
Safety. Other than the local tolerability reactions reported above, none of the patients experienced any adverse reactions or systemic side effects.
Points to Remember
• Development of visible signs and symptoms associated with inflammation are to be anticipated with the use of either imiquimod
5% cream or fluorouracil cream 0.5% (microsphere vehicle) for actinic keratosis.
• Signs of inflammation, such as erythema, tended to develop earlier in the group treated with topical 5-fluorouracil (within 1 week) as compared to those treated with topical imiquimod (within 2 weeks). By endpoint, visible signs of inflammation were similar in frequency and intensity among both treated sides.
• Symptoms such as burning, stinging, pruritus and pain tended to be more common and of greater severity in the group treated with topical 5-fluorouracil as compared to imiquimod-treated patients. Symptoms graded as severe were uncommon, and were reported
in two patients treated with 5-fluoruracil 0.5% cream (one pain, one pruritus).
• Imiquimod was preferred over 5-fluorouracil by the majority of patients.
Topical imiquimod 5% cream and 5-fluorouracil 0.5% microsphere cream are used for treatment of actinic keratosis. Yet to date, no blinded trials have directly compared the severity of symptoms associated with these two agents. Visible inflammation in the region of application is common during treatment with either of these therapies, although some literature has suggested that the severity of symptomatology (eg burning, stinging, pain) differs between the two agents.
This article reports on application-site tolerability results from an investigator-blinded, 4-week, randomized, bilateral comparison trial of imiquimod 5% cream (Aldara) applied 3 times per week (n=30) and 5-fluorouracil 0.5% cream (Carac) applied once daily (n=30) to the forehead region, cheeks or dorsum of the hands of adult patients with actinic keratosis. Patients were assessed weekly over 4 weeks using a four-point scale (none, mild, moderate, severe) to individually evaluate visible signs of inflammation, including erythema, erosion, crusting and edema. Participants used a daily subject diary to individually assess signs (such as erythema, oozing, scabbing) and symptoms (including burning, stinging, pruritus, pain), and patients reported on their preferred treatment.
Background
Topical imiquimod 5% cream and topical 5-fluorouracil (5-FU) 0.5% cream, formulated in a porous microsphere vehicle, are both approved by the FDA for treating actinic keratosis (AK) based on proven efficacy and safety in Phase III pivotal trials.1,2
Recommended use of topical 5-FU 0.5% for AK is once daily for up to 4 weeks, with continued treatment up to 4 weeks reported to result in greater lesion reduction.2
The approved treatment regimen for use of topical imiquimod for AK is application two times per week for 16 weeks, although several other regimens have been recommended in the literature.3 Cycle therapy with topical imiquimod has been suggested as a practical method of use for AK.3,4 A single cycle of imiquimod is application three times per week for 4 weeks followed by 4 weeks off of therapy (“4 weeks on, 4 weeks off”). In one study, a single cycle of treatment, which is essentially 4 weeks of active therapy followed by a 4-week rest period, produced complete clearance of 46% of treated cosmetic units.
Therapy with topical imiquimod or 5-FU 0.5% cream characteristically produces varying degrees of visible inflammation characterized by erythema, crusting and in some cases erosion.1-5 Associated symptoms may include stinging, burning and pruritus.
One split-face, single-blind, randomized trial reported greater tolerability with the 5-FU 0.5% as compared to 5-FU 5% cream for treatment of AK.5
There has been some suggestion based on clinical observation that despite the presence of visible inflammation with both therapies for AK, symptomatology is usually less severe with topical imiquimod as compared to topical 5-FU therapy.6 Well-designed controlled studies are needed to further evaluate this clinical observation.
Mechanisms of Action
Despite the presence of visible inflammation observed after use of either agent, it is important to recognize that 5-fluorouracil and imiquimod work through different mechanisms of action.
5-fluorouracil is a chemotherapeutic agent that produces direct cytotoxicity preferentially affecting more actively dividing cells, thus inducing an inflammatory reaction.
Imiquimod facilitates and augments both innate and acquired immune responses with production of multiple cytokines and infiltration of predominantly lymphocytes within the region of application which are directed against the treated disease (ie. AK). Therefore, the visible inflammation occurring in association with imiquimod application reflects an inflammatory response.
The following discusses tolerability results from the aforementioned investigator-blinded, side-to-side comparison of imiquimod 5% cream applied three times weekly for 4 weeks and 5-FU 0.5% cream applied daily for 4 weeks. Investigator and patient assessments were completed during the study.
REVIEWING THE STUDY SPECIFICS
Inclusion Criteria
• Male or female adult patients
• Symmetric involvement with AK of forehead, cheeks and dorsal hands (affected forearms also included if symmetric involvement was present) Symmetry was defined as a minimum of eight AKs in each treatment area (+/- two AK difference between treated sides) at baseline.
• Affirmation of informed consent from patients.
Exclusion Criteria
• Use of topical therapy for AK other than sunscreen protection within 6 months of baseline evaluation.
• Use of topical corticosteroids on affected areas within 30 days of baseline evaluation and throughout trial.
• Use of any systemic immunosuppressive or anti-inflammatory therapy within 30 days of baseline evaluation and throughout trial.
• History of previous treatment with topical imiquimod or topical 5-FU.
• A clinically significant skin condition that was determined by the investigator to interfere with study evaluation or participation.
• Pregnant or nursing female patients.
Study Design
• Investigator-blinded, bilateral comparative 4-week trial.
• Symmetric involvement with AK on the forehead, cheeks or dorsal hands (forearms included if symmetrically involved.
• Treatment sides randomized.
Subject Disposition
• 30 adult Caucasian patients; 19 males, 11 females; mean age 58 years (range 44 to 71 years); all 30 patients completed the trial.
• Symmetric involvement with AK of forehead (including temple region), cheeks or dorsal hands (forearms included if symmetrically involved).
• Treatment sides were randomized and maintained consistently throughout the study. Only a single designated anatomic area on each side was treated per patient.
• Treatment areas included forehead (n=7), cheeks (n=4), dorsal hands with forearms (n=12) and dorsal hands without forearms (n=7).
• Treatments were as follows:
• Imiquimod 5% cream applied three times per week x 4 weeks to one side.
• Fluorouracil 0.5% cream applied once daily x 4 weeks to opposite side.
Assessments
• Patients evaluated at baseline, week 1, week 2, week 3 and week 4. Parameters evaluated and graded included erythema, edema, crusting and erosion (see Table 1).
• Patients instructed to maintain daily log and grading of each of the following parameters: visible redness, scabbing, oozing (exudation), stinging, burning, pain, itching.
• At study endpoint, patients were asked to indicate which treatment they preferred and if they would repeat therapy with either agent in the future.
Results
The results of the trial are tabulated in Tables 3 through 6.
Patient Preference. When queried regarding preference, 15 patients preferred imiquimod, 8 patients preferred 5-FU 0.5%, and 7 patients stated no preference. With regard to use in the future if a treatment for AK is needed, 27 patients stated they would be willing to use imiquimod and 21 patients stated they would be willing to use 5-FU 0.5%.
Safety. Other than the local tolerability reactions reported above, none of the patients experienced any adverse reactions or systemic side effects.
Points to Remember
• Development of visible signs and symptoms associated with inflammation are to be anticipated with the use of either imiquimod
5% cream or fluorouracil cream 0.5% (microsphere vehicle) for actinic keratosis.
• Signs of inflammation, such as erythema, tended to develop earlier in the group treated with topical 5-fluorouracil (within 1 week) as compared to those treated with topical imiquimod (within 2 weeks). By endpoint, visible signs of inflammation were similar in frequency and intensity among both treated sides.
• Symptoms such as burning, stinging, pruritus and pain tended to be more common and of greater severity in the group treated with topical 5-fluorouracil as compared to imiquimod-treated patients. Symptoms graded as severe were uncommon, and were reported
in two patients treated with 5-fluoruracil 0.5% cream (one pain, one pruritus).
• Imiquimod was preferred over 5-fluorouracil by the majority of patients.
Topical imiquimod 5% cream and 5-fluorouracil 0.5% microsphere cream are used for treatment of actinic keratosis. Yet to date, no blinded trials have directly compared the severity of symptoms associated with these two agents. Visible inflammation in the region of application is common during treatment with either of these therapies, although some literature has suggested that the severity of symptomatology (eg burning, stinging, pain) differs between the two agents.
This article reports on application-site tolerability results from an investigator-blinded, 4-week, randomized, bilateral comparison trial of imiquimod 5% cream (Aldara) applied 3 times per week (n=30) and 5-fluorouracil 0.5% cream (Carac) applied once daily (n=30) to the forehead region, cheeks or dorsum of the hands of adult patients with actinic keratosis. Patients were assessed weekly over 4 weeks using a four-point scale (none, mild, moderate, severe) to individually evaluate visible signs of inflammation, including erythema, erosion, crusting and edema. Participants used a daily subject diary to individually assess signs (such as erythema, oozing, scabbing) and symptoms (including burning, stinging, pruritus, pain), and patients reported on their preferred treatment.
Background
Topical imiquimod 5% cream and topical 5-fluorouracil (5-FU) 0.5% cream, formulated in a porous microsphere vehicle, are both approved by the FDA for treating actinic keratosis (AK) based on proven efficacy and safety in Phase III pivotal trials.1,2
Recommended use of topical 5-FU 0.5% for AK is once daily for up to 4 weeks, with continued treatment up to 4 weeks reported to result in greater lesion reduction.2
The approved treatment regimen for use of topical imiquimod for AK is application two times per week for 16 weeks, although several other regimens have been recommended in the literature.3 Cycle therapy with topical imiquimod has been suggested as a practical method of use for AK.3,4 A single cycle of imiquimod is application three times per week for 4 weeks followed by 4 weeks off of therapy (“4 weeks on, 4 weeks off”). In one study, a single cycle of treatment, which is essentially 4 weeks of active therapy followed by a 4-week rest period, produced complete clearance of 46% of treated cosmetic units.
Therapy with topical imiquimod or 5-FU 0.5% cream characteristically produces varying degrees of visible inflammation characterized by erythema, crusting and in some cases erosion.1-5 Associated symptoms may include stinging, burning and pruritus.
One split-face, single-blind, randomized trial reported greater tolerability with the 5-FU 0.5% as compared to 5-FU 5% cream for treatment of AK.5
There has been some suggestion based on clinical observation that despite the presence of visible inflammation with both therapies for AK, symptomatology is usually less severe with topical imiquimod as compared to topical 5-FU therapy.6 Well-designed controlled studies are needed to further evaluate this clinical observation.
Mechanisms of Action
Despite the presence of visible inflammation observed after use of either agent, it is important to recognize that 5-fluorouracil and imiquimod work through different mechanisms of action.
5-fluorouracil is a chemotherapeutic agent that produces direct cytotoxicity preferentially affecting more actively dividing cells, thus inducing an inflammatory reaction.
Imiquimod facilitates and augments both innate and acquired immune responses with production of multiple cytokines and infiltration of predominantly lymphocytes within the region of application which are directed against the treated disease (ie. AK). Therefore, the visible inflammation occurring in association with imiquimod application reflects an inflammatory response.
The following discusses tolerability results from the aforementioned investigator-blinded, side-to-side comparison of imiquimod 5% cream applied three times weekly for 4 weeks and 5-FU 0.5% cream applied daily for 4 weeks. Investigator and patient assessments were completed during the study.
REVIEWING THE STUDY SPECIFICS
Inclusion Criteria
• Male or female adult patients
• Symmetric involvement with AK of forehead, cheeks and dorsal hands (affected forearms also included if symmetric involvement was present) Symmetry was defined as a minimum of eight AKs in each treatment area (+/- two AK difference between treated sides) at baseline.
• Affirmation of informed consent from patients.
Exclusion Criteria
• Use of topical therapy for AK other than sunscreen protection within 6 months of baseline evaluation.
• Use of topical corticosteroids on affected areas within 30 days of baseline evaluation and throughout trial.
• Use of any systemic immunosuppressive or anti-inflammatory therapy within 30 days of baseline evaluation and throughout trial.
• History of previous treatment with topical imiquimod or topical 5-FU.
• A clinically significant skin condition that was determined by the investigator to interfere with study evaluation or participation.
• Pregnant or nursing female patients.
Study Design
• Investigator-blinded, bilateral comparative 4-week trial.
• Symmetric involvement with AK on the forehead, cheeks or dorsal hands (forearms included if symmetrically involved.
• Treatment sides randomized.
Subject Disposition
• 30 adult Caucasian patients; 19 males, 11 females; mean age 58 years (range 44 to 71 years); all 30 patients completed the trial.
• Symmetric involvement with AK of forehead (including temple region), cheeks or dorsal hands (forearms included if symmetrically involved).
• Treatment sides were randomized and maintained consistently throughout the study. Only a single designated anatomic area on each side was treated per patient.
• Treatment areas included forehead (n=7), cheeks (n=4), dorsal hands with forearms (n=12) and dorsal hands without forearms (n=7).
• Treatments were as follows:
• Imiquimod 5% cream applied three times per week x 4 weeks to one side.
• Fluorouracil 0.5% cream applied once daily x 4 weeks to opposite side.
Assessments
• Patients evaluated at baseline, week 1, week 2, week 3 and week 4. Parameters evaluated and graded included erythema, edema, crusting and erosion (see Table 1).
• Patients instructed to maintain daily log and grading of each of the following parameters: visible redness, scabbing, oozing (exudation), stinging, burning, pain, itching.
• At study endpoint, patients were asked to indicate which treatment they preferred and if they would repeat therapy with either agent in the future.
Results
The results of the trial are tabulated in Tables 3 through 6.
Patient Preference. When queried regarding preference, 15 patients preferred imiquimod, 8 patients preferred 5-FU 0.5%, and 7 patients stated no preference. With regard to use in the future if a treatment for AK is needed, 27 patients stated they would be willing to use imiquimod and 21 patients stated they would be willing to use 5-FU 0.5%.
Safety. Other than the local tolerability reactions reported above, none of the patients experienced any adverse reactions or systemic side effects.
Points to Remember
• Development of visible signs and symptoms associated with inflammation are to be anticipated with the use of either imiquimod
5% cream or fluorouracil cream 0.5% (microsphere vehicle) for actinic keratosis.
• Signs of inflammation, such as erythema, tended to develop earlier in the group treated with topical 5-fluorouracil (within 1 week) as compared to those treated with topical imiquimod (within 2 weeks). By endpoint, visible signs of inflammation were similar in frequency and intensity among both treated sides.
• Symptoms such as burning, stinging, pruritus and pain tended to be more common and of greater severity in the group treated with topical 5-fluorouracil as compared to imiquimod-treated patients. Symptoms graded as severe were uncommon, and were reported
in two patients treated with 5-fluoruracil 0.5% cream (one pain, one pruritus).
• Imiquimod was preferred over 5-fluorouracil by the majority of patients.
