Topical Therapy for Actinic Keratoses, II: Diclofenac, Colchicine, and Retinoids

Actinic keratoses (AKs) are evolving, malignant cutaneous neoplasms. AKs can be treated with physical or destructive methods and by topical therapies. This article is the second in a 2-part series of current topical therapeutic options for AKs and discusses topical diclofenac, colchicine, and retinoids. The first part focused on topical 5-fluorouracil and imiquimod.

Actinic keratoses (AKs) are the most common neoplastic skin lesions detected in individuals with Fitzpatrick skin type I or II. AKs appear as papules in a vast spectrum of sizes, shapes, colors, and other characteristics. Their size and shape can range from a well-circumscribed, single millimeter papule to an irregularly shaped lesion that can span several centimeters. These neoplasms can be flesh colored, red, or pigmented and also can scale or become hyperkeratotic. The most common sites for these lesions are the face, ears, scalp, neck, forearms, and hands. Chronic, repetitive UV exposure results in repetitive cycles of DNA damage. Eventually, these cycles of damage and repair spawn a significant unrecoverable error.

To combat this very common lesion, a host of topical preparations has been investigated. Therapies include 5-fluorouracil, imiquimod, diclofenac, colchicine and retinoids. This second part of a 2-part review focuses on topical diclofenac, colchicine, and retinoids (Table 1).

Diclofenac Diclofenac, a nonsteroidal anti-inflammatory drug, also has been evaluated for the treatment of AKs (Table 2). 1-4 Currently, this drug's mechanism of action in the treatment of these precancerous lesions is not clearly understood. However, there are current research efforts exploring the theory that diclofenac's clinical effect occurs through the inhibition of the cyclooxygenase enzymes, which decrease the downstream by-products of arachidonic acid metabolism. Some of these by-products control overall immunosurveillance, the inhibition of apoptosis, and up-regulation of the invasive ability of tumor cells.7-10

Rivers and McLean1 conducted a 29-patient, open-label study using 3% diclofenac in 2.5% hyaluronic acid gel applied twice daily to 1 or more target lesions. The AKs were treated until they resolved or until they had been treated for 180 days. The 27 patients that completed the study had treatment times ranging from 33 to 176 days. At the 30-day posttreatment examination, 22 of the 27 patients (81%) had complete resolution of the target lesions. Generally, the preparation was well tolerated, though in 7 of the original patients (24%), an irritant-type contact dermatitis confined to the treatment site developed.1

Wolf et al2 examined the efficacy and safety of 3% diclofenac in 2.5% hyaluronan gel in 120 subjects. During the first 3 months of this study, patients applied the cream to the target area twice a day. Follow-up evaluations occurred one month after the treatment period had been completed. Then, 50% of treatment patients and 20% of placebo patients experienced total clearance of target AKs present at the initiation of the study. Further, 47% of treatment patients had total clearance, while only 19% of placebo patients experienced total clearance. The difference between the number of treatment patients and placebo patients who achieved these response levels was significant in both instances (P30%)(P=.001). No significant treatment benefit was seen for lesions on the scalp or upper extremities.28

Similarly, Moglia et al29 treated 18 patients with facial AKs with topical retinoid fenretinide, 4-HPR (N-[4-hydroxyphenyl]retinamide), twice daily for 3 months. Following this treatment period, complete regression of the lesions was observed in 56% (10) of patients. Further, partial regression was observed in an additional 44% (8) of patients. Eight patients (44%) relapsed within 3 months after treatment. In addition, only 2 patients (11%) showed complete regression 6 months later. No adverse effects were observed. Also, it was found that baseline plasma retinol levels were lower than in healthy subjects, which suggest that reduced retinol levels might be involved in the pathology of AKs.29

In a double-blind, randomized, within-patient comparative study, the efficacy and tolerability of Ro 14-9706 (an arotinoid methyl sulfone) for the treatment of AKs were compared with those of tretinoin.30 Twenty-six patients with more than 3 lesions on each side of the face were included in the study. Patients applied each agent twice daily for 16 weeks as a 0.05% cream to opposite sides of their face. The mean percentage decrease in the number of AKs was assessed before treatment and at weekly intervals during the treatment period. The mean percentage decrease in the number of AKs was 37.8% for areas treated with Ro 14-9706 and 30.3% for areas treated with tretinoin. These decreases were significantly different from baseline (P<.01) but not from each other. There was an associated severe erythema in 50% (13) of patients treated with tretinoin and severe scaling in 23% (6), whereas Ro 14-9706 was better tolerated, with only a slight or absent inflammation.30

Studies also have examined the efficacy of high-dose systemic etretinate for the treatment of AKs. Moriarty et al31 conducted a double-blind crossover study of 50 patients with AKs who were treated with a 4-month course of oral etretinate. They concluded that 37 of the 44 patients (84%) who completed treatment with etretinate versus only 2 out of 42 patients (5%) in the placebo group had a complete or partial response. Unfortunately, the systemic toxicity of retinoids discourages their use for long-term treatment at high doses.31

Retinoids also enhance the effectiveness of 5-fluorouracil. In a randomized, double-blind controlled study by Bercovitch,32 19 patients applied 5% fluorouracil cream to AKs on each arm twice daily, followed by nightly application of 0.05% tretinoin cream to one arm and a control cream to the other arm, until discomfort precluded further applications. Three months after treatment, the tretinoin-treated arms had 3.4±2.6 AKs versus 15.7±6.1 AKs before treatment. In contrast, the control arm had 4.2±2.5 lesions after treatment compared with 15.3±6.9 AKs before treatment (P<.04).32 Similar results were found by Sander et al34 as to a synergistic effect in the treatment of disseminated AKs on photodamaged skin when low-dose isotretinoin and topical 5-fluorouracil are combined. As with etretinate, such combination treatment regimens have limited usage secondary to such side effects as pain, irritation, and bleeding. These symptoms were the extent of adverse effects seen in treatment with retinoids for AK in the majority of cases reviewed.34

Conclusion

While countless individuals are diagnosed with AKs, research efforts have revealed an encouraging array of topical and semi-invasive treatment options that allow the dermatologist and patient to select a therapy that specifically suits the patient’s needs by balancing both therapeutic and aesthetic outcomes in accordance with the patient’s lifestyle. Topical treatments currently available to treat AKs offer the benefits of relative ease of administration and minimal incidence of severe adverse effects. More important, these novel and standard treatments allow dermatologists to alleviate the apprehension and inconvenience experienced by patients affected by these lesions.

Actinic keratoses (AKs) are evolving, malignant cutaneous neoplasms. AKs can be treated with physical or destructive methods and by topical therapies. This article is the second in a 2-part series of current topical therapeutic options for AKs and discusses topical diclofenac, colchicine, and retinoids. The first part focused on topical 5-fluorouracil and imiquimod.

Actinic keratoses (AKs) are the most common neoplastic skin lesions detected in individuals with Fitzpatrick skin type I or II. AKs appear as papules in a vast spectrum of sizes, shapes, colors, and other characteristics. Their size and shape can range from a well-circumscribed, single millimeter papule to an irregularly shaped lesion that can span several centimeters. These neoplasms can be flesh colored, red, or pigmented and also can scale or become hyperkeratotic. The most common sites for these lesions are the face, ears, scalp, neck, forearms, and hands. Chronic, repetitive UV exposure results in repetitive cycles of DNA damage. Eventually, these cycles of damage and repair spawn a significant unrecoverable error.

To combat this very common lesion, a host of topical preparations has been investigated. Therapies include 5-fluorouracil, imiquimod, diclofenac, colchicine and retinoids. This second part of a 2-part review focuses on topical diclofenac, colchicine, and retinoids (Table 1).

Diclofenac Diclofenac, a nonsteroidal anti-inflammatory drug, also has been evaluated for the treatment of AKs (Table 2). 1-4 Currently, this drug's mechanism of action in the treatment of these precancerous lesions is not clearly understood. However, there are current research efforts exploring the theory that diclofenac's clinical effect occurs through the inhibition of the cyclooxygenase enzymes, which decrease the downstream by-products of arachidonic acid metabolism. Some of these by-products control overall immunosurveillance, the inhibition of apoptosis, and up-regulation of the invasive ability of tumor cells.7-10

Rivers and McLean1 conducted a 29-patient, open-label study using 3% diclofenac in 2.5% hyaluronic acid gel applied twice daily to 1 or more target lesions. The AKs were treated until they resolved or until they had been treated for 180 days. The 27 patients that completed the study had treatment times ranging from 33 to 176 days. At the 30-day posttreatment examination, 22 of the 27 patients (81%) had complete resolution of the target lesions. Generally, the preparation was well tolerated, though in 7 of the original patients (24%), an irritant-type contact dermatitis confined to the treatment site developed.1

Wolf et al2 examined the efficacy and safety of 3% diclofenac in 2.5% hyaluronan gel in 120 subjects. During the first 3 months of this study, patients applied the cream to the target area twice a day. Follow-up evaluations occurred one month after the treatment period had been completed. Then, 50% of treatment patients and 20% of placebo patients experienced total clearance of target AKs present at the initiation of the study. Further, 47% of treatment patients had total clearance, while only 19% of placebo patients experienced total clearance. The difference between the number of treatment patients and placebo patients who achieved these response levels was significant in both instances (P30%)(P=.001). No significant treatment benefit was seen for lesions on the scalp or upper extremities.28

Similarly, Moglia et al29 treated 18 patients with facial AKs with topical retinoid fenretinide, 4-HPR (N-[4-hydroxyphenyl]retinamide), twice daily for 3 months. Following this treatment period, complete regression of the lesions was observed in 56% (10) of patients. Further, partial regression was observed in an additional 44% (8) of patients. Eight patients (44%) relapsed within 3 months after treatment. In addition, only 2 patients (11%) showed complete regression 6 months later. No adverse effects were observed. Also, it was found that baseline plasma retinol levels were lower than in healthy subjects, which suggest that reduced retinol levels might be involved in the pathology of AKs.29

In a double-blind, randomized, within-patient comparative study, the efficacy and tolerability of Ro 14-9706 (an arotinoid methyl sulfone) for the treatment of AKs were compared with those of tretinoin.30 Twenty-six patients with more than 3 lesions on each side of the face were included in the study. Patients applied each agent twice daily for 16 weeks as a 0.05% cream to opposite sides of their face. The mean percentage decrease in the number of AKs was assessed before treatment and at weekly intervals during the treatment period. The mean percentage decrease in the number of AKs was 37.8% for areas treated with Ro 14-9706 and 30.3% for areas treated with tretinoin. These decreases were significantly different from baseline (P<.01) but not from each other. There was an associated severe erythema in 50% (13) of patients treated with tretinoin and severe scaling in 23% (6), whereas Ro 14-9706 was better tolerated, with only a slight or absent inflammation.30

Studies also have examined the efficacy of high-dose systemic etretinate for the treatment of AKs. Moriarty et al31 conducted a double-blind crossover study of 50 patients with AKs who were treated with a 4-month course of oral etretinate. They concluded that 37 of the 44 patients (84%) who completed treatment with etretinate versus only 2 out of 42 patients (5%) in the placebo group had a complete or partial response. Unfortunately, the systemic toxicity of retinoids discourages their use for long-term treatment at high doses.31

Retinoids also enhance the effectiveness of 5-fluorouracil. In a randomized, double-blind controlled study by Bercovitch,32 19 patients applied 5% fluorouracil cream to AKs on each arm twice daily, followed by nightly application of 0.05% tretinoin cream to one arm and a control cream to the other arm, until discomfort precluded further applications. Three months after treatment, the tretinoin-treated arms had 3.4±2.6 AKs versus 15.7±6.1 AKs before treatment. In contrast, the control arm had 4.2±2.5 lesions after treatment compared with 15.3±6.9 AKs before treatment (P<.04).32 Similar results were found by Sander et al34 as to a synergistic effect in the treatment of disseminated AKs on photodamaged skin when low-dose isotretinoin and topical 5-fluorouracil are combined. As with etretinate, such combination treatment regimens have limited usage secondary to such side effects as pain, irritation, and bleeding. These symptoms were the extent of adverse effects seen in treatment with retinoids for AK in the majority of cases reviewed.34

Conclusion

While countless individuals are diagnosed with AKs, research efforts have revealed an encouraging array of topical and semi-invasive treatment options that allow the dermatologist and patient to select a therapy that specifically suits the patient’s needs by balancing both therapeutic and aesthetic outcomes in accordance with the patient’s lifestyle. Topical treatments currently available to treat AKs offer the benefits of relative ease of administration and minimal incidence of severe adverse effects. More important, these novel and standard treatments allow dermatologists to alleviate the apprehension and inconvenience experienced by patients affected by these lesions.

Actinic keratoses (AKs) are evolving, malignant cutaneous neoplasms. AKs can be treated with physical or destructive methods and by topical therapies. This article is the second in a 2-part series of current topical therapeutic options for AKs and discusses topical diclofenac, colchicine, and retinoids. The first part focused on topical 5-fluorouracil and imiquimod.

Actinic keratoses (AKs) are the most common neoplastic skin lesions detected in individuals with Fitzpatrick skin type I or II. AKs appear as papules in a vast spectrum of sizes, shapes, colors, and other characteristics. Their size and shape can range from a well-circumscribed, single millimeter papule to an irregularly shaped lesion that can span several centimeters. These neoplasms can be flesh colored, red, or pigmented and also can scale or become hyperkeratotic. The most common sites for these lesions are the face, ears, scalp, neck, forearms, and hands. Chronic, repetitive UV exposure results in repetitive cycles of DNA damage. Eventually, these cycles of damage and repair spawn a significant unrecoverable error.

To combat this very common lesion, a host of topical preparations has been investigated. Therapies include 5-fluorouracil, imiquimod, diclofenac, colchicine and retinoids. This second part of a 2-part review focuses on topical diclofenac, colchicine, and retinoids (Table 1).

Diclofenac Diclofenac, a nonsteroidal anti-inflammatory drug, also has been evaluated for the treatment of AKs (Table 2). 1-4 Currently, this drug's mechanism of action in the treatment of these precancerous lesions is not clearly understood. However, there are current research efforts exploring the theory that diclofenac's clinical effect occurs through the inhibition of the cyclooxygenase enzymes, which decrease the downstream by-products of arachidonic acid metabolism. Some of these by-products control overall immunosurveillance, the inhibition of apoptosis, and up-regulation of the invasive ability of tumor cells.7-10

Rivers and McLean1 conducted a 29-patient, open-label study using 3% diclofenac in 2.5% hyaluronic acid gel applied twice daily to 1 or more target lesions. The AKs were treated until they resolved or until they had been treated for 180 days. The 27 patients that completed the study had treatment times ranging from 33 to 176 days. At the 30-day posttreatment examination, 22 of the 27 patients (81%) had complete resolution of the target lesions. Generally, the preparation was well tolerated, though in 7 of the original patients (24%), an irritant-type contact dermatitis confined to the treatment site developed.1

Wolf et al2 examined the efficacy and safety of 3% diclofenac in 2.5% hyaluronan gel in 120 subjects. During the first 3 months of this study, patients applied the cream to the target area twice a day. Follow-up evaluations occurred one month after the treatment period had been completed. Then, 50% of treatment patients and 20% of placebo patients experienced total clearance of target AKs present at the initiation of the study. Further, 47% of treatment patients had total clearance, while only 19% of placebo patients experienced total clearance. The difference between the number of treatment patients and placebo patients who achieved these response levels was significant in both instances (P30%)(P=.001). No significant treatment benefit was seen for lesions on the scalp or upper extremities.28

Similarly, Moglia et al29 treated 18 patients with facial AKs with topical retinoid fenretinide, 4-HPR (N-[4-hydroxyphenyl]retinamide), twice daily for 3 months. Following this treatment period, complete regression of the lesions was observed in 56% (10) of patients. Further, partial regression was observed in an additional 44% (8) of patients. Eight patients (44%) relapsed within 3 months after treatment. In addition, only 2 patients (11%) showed complete regression 6 months later. No adverse effects were observed. Also, it was found that baseline plasma retinol levels were lower than in healthy subjects, which suggest that reduced retinol levels might be involved in the pathology of AKs.29

In a double-blind, randomized, within-patient comparative study, the efficacy and tolerability of Ro 14-9706 (an arotinoid methyl sulfone) for the treatment of AKs were compared with those of tretinoin.30 Twenty-six patients with more than 3 lesions on each side of the face were included in the study. Patients applied each agent twice daily for 16 weeks as a 0.05% cream to opposite sides of their face. The mean percentage decrease in the number of AKs was assessed before treatment and at weekly intervals during the treatment period. The mean percentage decrease in the number of AKs was 37.8% for areas treated with Ro 14-9706 and 30.3% for areas treated with tretinoin. These decreases were significantly different from baseline (P<.01) but not from each other. There was an associated severe erythema in 50% (13) of patients treated with tretinoin and severe scaling in 23% (6), whereas Ro 14-9706 was better tolerated, with only a slight or absent inflammation.30

Studies also have examined the efficacy of high-dose systemic etretinate for the treatment of AKs. Moriarty et al31 conducted a double-blind crossover study of 50 patients with AKs who were treated with a 4-month course of oral etretinate. They concluded that 37 of the 44 patients (84%) who completed treatment with etretinate versus only 2 out of 42 patients (5%) in the placebo group had a complete or partial response. Unfortunately, the systemic toxicity of retinoids discourages their use for long-term treatment at high doses.31

Retinoids also enhance the effectiveness of 5-fluorouracil. In a randomized, double-blind controlled study by Bercovitch,32 19 patients applied 5% fluorouracil cream to AKs on each arm twice daily, followed by nightly application of 0.05% tretinoin cream to one arm and a control cream to the other arm, until discomfort precluded further applications. Three months after treatment, the tretinoin-treated arms had 3.4±2.6 AKs versus 15.7±6.1 AKs before treatment. In contrast, the control arm had 4.2±2.5 lesions after treatment compared with 15.3±6.9 AKs before treatment (P<.04).32 Similar results were found by Sander et al34 as to a synergistic effect in the treatment of disseminated AKs on photodamaged skin when low-dose isotretinoin and topical 5-fluorouracil are combined. As with etretinate, such combination treatment regimens have limited usage secondary to such side effects as pain, irritation, and bleeding. These symptoms were the extent of adverse effects seen in treatment with retinoids for AK in the majority of cases reviewed.34

Conclusion

While countless individuals are diagnosed with AKs, research efforts have revealed an encouraging array of topical and semi-invasive treatment options that allow the dermatologist and patient to select a therapy that specifically suits the patient’s needs by balancing both therapeutic and aesthetic outcomes in accordance with the patient’s lifestyle. Topical treatments currently available to treat AKs offer the benefits of relative ease of administration and minimal incidence of severe adverse effects. More important, these novel and standard treatments allow dermatologists to alleviate the apprehension and inconvenience experienced by patients affected by these lesions.