These side effects must be tolerated by the patient, as proper adherence is necessary to maintain efficacy. Topical 5-FU is available in 0.5% (Carac), 1% (Fluoroplex), 4% (Tolak), and 5% (Efudex) formulations; lower concentrations of 5-FU aim to balance efficacy with an acceptable side effect profile.12
5% 5-FU (Efudex) is applied twice daily to areas of skin with multiple AKs for a duration of 2 to 4 weeks. As the most potent drug in its class, 5% 5-FU is relatively less tolerated compared to the other available formulations of 5-FU. A comparison of 4% 5-FU applied once daily to either generic 5% 5-FU applied twice daily or vehicle cream found that application site reactions such as irritation, pain, erythema, pruritus, and edema occurred in all participants in both the 4% and 5% 5-FU groups at 2 weeks and 4 weeks of treatment. However, 4% 5-FU was more tolerable, and less severe stinging, burning, crusting, and itch at the site of application was observed compared with 5% 5-FU.16 Furthermore, 14.9% of subjects discontinued use of 5%-FU compared with 10.1% of subjects who discontinued use of 4% 5-FU.16
Phase III clinical trials evaluating the efficacy and safety of 0.5% 5-FU also found a similar, but more tolerable, side effect profile compared to the more potent 4% and 5% formulations. Application site erythema (93.4% of participants), dryness (83.3%), and burning (74.7%) were commonly experienced in patients applying 0.5% 5-FU for 1-, 2-, and 4-week treatment courses.17 The majority of patients in the 1-week treatment group experienced mild LSRs, and the majority of patients in the 2- and 4-week treatment groups experienced mild-tomoderate LSRs.17 This is in contrast to pivotal phase III trials evaluating the safety and efficacy of 4% 5-FU (Tolak), in which the proportion of patients who experienced severe erythema, dryness, and burning in a 4-week daily treatment period was 44%, 24%, and 25%, respectively (n=397).18
A phase III trial sought to determine if pre-treatment with cryosurgery followed by a 1-week course of either Carac cream or Cetaphil cream maintained treatment efficacy while minimizing application-site adverse effects.19 Although patients receiving Carac reported significantly more LSRs compared to patients receiving Cetaphil, LSR severity was similar to the 1-week course of Carac cream and lower than the LSR severity observed in the 2- and 4-week courses of Carac evaluated in the pivotal phase III trials.19–21
Imiquimod
Imiquimod is a toll-like receptor (TLR) agonist which was first approved for the treatment of external genital and perianal warts caused by human papillomavirus (HPV); it stimulates TNF-a and IL-6 expression to leverage adaptive and immune pathways in anti-viral and anti-tumor responses. Its antilesional activity in AK and superficial basal cell carcinoma (sBCC) is mediated through both cytolytic and apoptoptic pathways which result in lesion destruction within the treatment field.22 LSRs such as erythema, scabbing, crusting, dryness, erosion, ulceration, edema, vesiculation, and weeping may be experienced with topical application of imiquimod.23 The tolerability of imiquimod, much like the other topical agents reviewed, varies directly with its potency; topical imiquimod is available in 2.5% (Zyclara 2.5%), 3.75% (Zyclara 3.75%), and 5% (Aldara) formulations.
2 phase III trials of imiquimod 5% cream applied daily twice weekly vs thrice weekly evaluated application-site AEs such as itching (20.5% vs 28.9%), burning (5.6% vs 7.4%), pain (2.3% vs 3.7%), and tenderness (1.9% vs 2.1%).23,24 LSRs were experienced by nearly all patients in both studies, and the rates of severe LSRs followed a similar trend to the application-site AEs between twice vs thrice-weekly application in erythema (17.7% vs 33.2%) and flaking/scaling/dryness (7.4% vs 8.7%).23,24 4% of patients applying imiquimod 5% twice daily discontinued due to either AEs or LSRs, and 13.2% of patients in the study evaluating thrice weekly treatment discontinued.23,24
Application-site AEs and LSRs were evaluated in two phase III clinical trials in which imiquimod 2.5% and 3.75% cream formulations were applied daily for two 2-week or 3-week treatment cycles flanking one 2- or 3-week cycle off treatment.25,26 3.75% imiquimod applied in a 3-week treatment cycle was associated with the highest rates of applicationsite AEs (pruritus, irritation, pain, and swelling) and LSRs (erythema, edema, weeping/exudate, flaking/scaling/dryness, scabbing/crusting, and erosion/ulceration).26 A follow-up study at 14 months included patients from both previous trials with complete lesion clearance; only one patient in the 2-week/3.75% treatment arm had a treatment-related AE (scarring in treatment area).27
Ingenol Mebutate
Ingenol mebutate (Picato) is a macrocyclic diterpene ester derived from Euphorbia peplus and was approved in the US for the treatment of AK. Its mechanism of action is two-fold; first through destabilizing mitochondrial cell membranes and increasing intracellular calcium, resulting in lesional necrosis, and second through neutrophil activation via ongoing necrosis and antibody dependent cellular cytotoxicity (ADCC). Neutrophil activation triggers an “oxidative burst” which releases reactive oxygen species (ROS) and further eliminates remaining dysplastic cells.28 Ingenol mebutate is available in 0.015% and 0.05% formulations for treatment of AK on the face and trunk, respectively; duration of application is 3 days for the face and 2 days for the trunk. Commonly reported application-site AEs include pain and pruritus; LSRs such as erythema, scabbing, crusting, dryness, erosion, ulceration, edema, vesiculation, and weeping also may be observed.
5% 5-FU (Efudex) is applied twice daily to areas of skin with multiple AKs for a duration of 2 to 4 weeks. As the most potent drug in its class, 5% 5-FU is relatively less tolerated compared to the other available formulations of 5-FU. A comparison of 4% 5-FU applied once daily to either generic 5% 5-FU applied twice daily or vehicle cream found that application site reactions such as irritation, pain, erythema, pruritus, and edema occurred in all participants in both the 4% and 5% 5-FU groups at 2 weeks and 4 weeks of treatment. However, 4% 5-FU was more tolerable, and less severe stinging, burning, crusting, and itch at the site of application was observed compared with 5% 5-FU.16 Furthermore, 14.9% of subjects discontinued use of 5%-FU compared with 10.1% of subjects who discontinued use of 4% 5-FU.16
Phase III clinical trials evaluating the efficacy and safety of 0.5% 5-FU also found a similar, but more tolerable, side effect profile compared to the more potent 4% and 5% formulations. Application site erythema (93.4% of participants), dryness (83.3%), and burning (74.7%) were commonly experienced in patients applying 0.5% 5-FU for 1-, 2-, and 4-week treatment courses.17 The majority of patients in the 1-week treatment group experienced mild LSRs, and the majority of patients in the 2- and 4-week treatment groups experienced mild-tomoderate LSRs.17 This is in contrast to pivotal phase III trials evaluating the safety and efficacy of 4% 5-FU (Tolak), in which the proportion of patients who experienced severe erythema, dryness, and burning in a 4-week daily treatment period was 44%, 24%, and 25%, respectively (n=397).18
A phase III trial sought to determine if pre-treatment with cryosurgery followed by a 1-week course of either Carac cream or Cetaphil cream maintained treatment efficacy while minimizing application-site adverse effects.19 Although patients receiving Carac reported significantly more LSRs compared to patients receiving Cetaphil, LSR severity was similar to the 1-week course of Carac cream and lower than the LSR severity observed in the 2- and 4-week courses of Carac evaluated in the pivotal phase III trials.19–21
Imiquimod
Imiquimod is a toll-like receptor (TLR) agonist which was first approved for the treatment of external genital and perianal warts caused by human papillomavirus (HPV); it stimulates TNF-a and IL-6 expression to leverage adaptive and immune pathways in anti-viral and anti-tumor responses. Its antilesional activity in AK and superficial basal cell carcinoma (sBCC) is mediated through both cytolytic and apoptoptic pathways which result in lesion destruction within the treatment field.22 LSRs such as erythema, scabbing, crusting, dryness, erosion, ulceration, edema, vesiculation, and weeping may be experienced with topical application of imiquimod.23 The tolerability of imiquimod, much like the other topical agents reviewed, varies directly with its potency; topical imiquimod is available in 2.5% (Zyclara 2.5%), 3.75% (Zyclara 3.75%), and 5% (Aldara) formulations.
2 phase III trials of imiquimod 5% cream applied daily twice weekly vs thrice weekly evaluated application-site AEs such as itching (20.5% vs 28.9%), burning (5.6% vs 7.4%), pain (2.3% vs 3.7%), and tenderness (1.9% vs 2.1%).23,24 LSRs were experienced by nearly all patients in both studies, and the rates of severe LSRs followed a similar trend to the application-site AEs between twice vs thrice-weekly application in erythema (17.7% vs 33.2%) and flaking/scaling/dryness (7.4% vs 8.7%).23,24 4% of patients applying imiquimod 5% twice daily discontinued due to either AEs or LSRs, and 13.2% of patients in the study evaluating thrice weekly treatment discontinued.23,24
Application-site AEs and LSRs were evaluated in two phase III clinical trials in which imiquimod 2.5% and 3.75% cream formulations were applied daily for two 2-week or 3-week treatment cycles flanking one 2- or 3-week cycle off treatment.25,26 3.75% imiquimod applied in a 3-week treatment cycle was associated with the highest rates of applicationsite AEs (pruritus, irritation, pain, and swelling) and LSRs (erythema, edema, weeping/exudate, flaking/scaling/dryness, scabbing/crusting, and erosion/ulceration).26 A follow-up study at 14 months included patients from both previous trials with complete lesion clearance; only one patient in the 2-week/3.75% treatment arm had a treatment-related AE (scarring in treatment area).27
Ingenol Mebutate
Ingenol mebutate (Picato) is a macrocyclic diterpene ester derived from Euphorbia peplus and was approved in the US for the treatment of AK. Its mechanism of action is two-fold; first through destabilizing mitochondrial cell membranes and increasing intracellular calcium, resulting in lesional necrosis, and second through neutrophil activation via ongoing necrosis and antibody dependent cellular cytotoxicity (ADCC). Neutrophil activation triggers an “oxidative burst” which releases reactive oxygen species (ROS) and further eliminates remaining dysplastic cells.28 Ingenol mebutate is available in 0.015% and 0.05% formulations for treatment of AK on the face and trunk, respectively; duration of application is 3 days for the face and 2 days for the trunk. Commonly reported application-site AEs include pain and pruritus; LSRs such as erythema, scabbing, crusting, dryness, erosion, ulceration, edema, vesiculation, and weeping also may be observed.
