What’s old is new again for actinic keratoses treatment

DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.

Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.

Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."

As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."

Other topical preparations for actinic keratoses on the market include:

• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."

Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.

• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.

Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.

"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."

Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.

• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.

In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."

Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."

Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.

[email protected]

DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.

Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.

Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."

As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."

Other topical preparations for actinic keratoses on the market include:

• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."

Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.

• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.

Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.

"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."

Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.

• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.

In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."

Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."

Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.

[email protected]

DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.

Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.

Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."

As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."

Other topical preparations for actinic keratoses on the market include:

• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."

Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.

• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.

Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.

"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."

Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.

• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.

In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."

Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."

Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.

[email protected]