Treatment Options for Actinic Keratoses



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Am Fam Physician. 2007 Sep 1;76(5):667-671.

  Patient information: See related handout on actinic keratoses, written by the authors of this article.

Actinic keratoses are rough, scaly lesions that commonly occur on sun-exposed areas of the skin. The prevalence of the condition increases with age. Actinic keratoses are thought to be carcinomas in situ, which can progress to squamous cell carcinomas. The decision to treat can be based on cosmetic reasons; symptom relief; or, most importantly, the prevention of malignancy and metastasis. Treatment options include ablative (destructive) therapies such as cryosurgery, curettage with electrosurgery, and photodynamic therapy. Topical therapies are used in patients with multiple lesions. Fluorouracil has been the traditional topical treatment for actinic keratoses, although imiquimod 5% cream and diclofenac 3% gel are effective alternative therapies. There are too few controlled trials comparing treatment modalities for physicians to make sound, evidence-based treatment decisions.

Actinic keratoses are lesions that begin in the epidermis on sun-exposed areas of the body. The lesions appear as rough, scaly patches that range in color from normal skin tone to reddish brown (Figures 1A and 1B). They are often circumscribed and are usually 1 mm to 2.5 cm in diameter, but they can be larger. Patients may present with a single, well-defined lesion or multiple, less-defined lesions covering a large area of skin. Several types of lesions may be present. Most lesions are asymptomatic, but some cause pruritus or a burning sensation.1

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

Actinic keratoses should be treated because of their potential to progress to squamous cell carcinomas.

C

811

Cryosurgery is an effective modality for treating solitary or multiple actinic keratoses.

C

1618

Curettage is an effective treatment for patients with a limited number of actinic keratoses, particularly thick, hyperkeratotic lesions.

C

20

Topical treatment should be considered for patients with multiple lesions.

C

16


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 612 or http://www.aafp.org/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

Actinic keratoses should be treated because of their potential to progress to squamous cell carcinomas.

C

811

Cryosurgery is an effective modality for treating solitary or multiple actinic keratoses.

C

1618

Curettage is an effective treatment for patients with a limited number of actinic keratoses, particularly thick, hyperkeratotic lesions.

C

20

Topical treatment should be considered for patients with multiple lesions.

C

16


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 612 or http://www.aafp.org/afpsort.xml.

Figure 1.

Actinic keratoses on (A) the hand and (B) the face.

Photos courtesy of Daniel A. Davis, MD.

View Large


Figure 1.

Actinic keratoses on (A) the hand and (B) the face.

Photos courtesy of Daniel A. Davis, MD.


Figure 1.

Actinic keratoses on (A) the hand and (B) the face.

Photos courtesy of Daniel A. Davis, MD.

Prevalence

Fair-skinned, blue-eyed persons living in sunny climates are most likely to develop actinic keratoses. The lesions take years to develop and usually occur in older persons; they are more common in men than in women.1 Persons with many years of extensive sun exposure are at the greatest risk. More than 80 percent of actinic keratoses occur on areas of the skin with the most sun exposure such as on the head, neck, forearms, and hands.24

It is estimated that 60 percent of predisposed persons older than 40 years have at least one actinic keratosis.5 Among white persons, the prevalence of the disease increases with age, ranging from less than 10 percent in persons 20 to 29 years of age to 75 percent in those 80 to 89 years of age.6,7

Risk of Cancer

Actinic keratoses, the most common pre-malignant lesions seen by dermatologists, have the potential to progress to squamous cell carcinomas.811 Although most actinic keratoses do not progress to cancer, and as many as 26 percent regress spontaneously,11 up to 60 percent of cutaneous squamous cell carcinomas arise from actinic keratoses.10

Estimates on the risk of actinic keratoses progressing to squamous cell carcinomas vary widely. A prospective, longitudinal study found the risk of progression to be 0.24 percent per year for each actinic keratosis.11 Because most patients have more than one actinic keratosis, another study used these data to determine that the risk of progression to squamous cell carcinoma is 6.1 to 10.2 percent over 10 years per person.12 Two additional studies show that keratoses are associated with squamous cell carcinomas 72 to 97 percent of the time.8,9

After progression to squamous cell carcinoma has occurred, the risk of metastasis is estimated to be 0.5 to 3.3 percent.13,14 One study found histologic evidence that actinic keratoses are present in 44 percent of squamous cell carcinomas that have metastasized.15

Treatment

Actinic keratoses may be treated for cosmetic reasons or for relief of associated symptoms, but the most compelling reason for treatment is to prevent squamous cell carcinomas. Treatment options include ablative (destructive) therapies or topical therapies in patients with multiple lesions.

CRYOSURGERY

Cryosurgery using liquid nitrogen is the most common modality for treating actinic keratoses, although compressed nitrous oxide or carbon dioxide is also used. Liquid nitrogen is sprayed directly on the lesions or applied using a cotton-tipped swab.

The procedure is highly effective, with reported cure rates between 75 and 99 percent16,17; however, correct technique is important. A study showed that a five-second treatment had a 39 percent cure rate, whereas a treatment of more than 20 seconds had an 83 percent cure rate.18

Cryosurgery is easily performed in the office setting, produces excellent cosmetic results, and is well tolerated. Potential adverse effects include infection, hypo- or hyperpigmentation, scarring, and hair loss; however, serious reactions are rare. Cryosurgery is best for treating thin, well-demarcated lesions and can be used to treat solitary lesions or small numbers of scattered lesions. Hyperkeratotic lesions are more resistant to cryosurgery and should be debrided before treatment.16,19

CURETTAGE

Curettage, which involves mechanically scraping away abnormal tissue using a sharp curette, is a highly effective modality for treating actinic keratoses. The procedure provides tissue for histologic evaluation but requires local anesthesia.20 Curettage is particularly useful for treating a limited number of actinic keratoses, especially thick, hyperkeratotic lesions. After curettage, electrosurgery may be used to destroy any remaining abnormal tissue and to provide hemostasis. Possible complications include infection, scarring, and hypo- or hyperpigmentation.

PHOTODYNAMIC THERAPY

Photodynamic therapy involves applying a photosensitizing agent to each actinic keratosis, followed by exposure to light of a specific wavelength; this leads to cell death.21 Protocols for using photodynamic therapy to treat actinic keratoses vary with regard to the photosensitizing agent; amount of application; and light source, intensity, and dose. Two protocols are approved for use in the United States.22

The use of the photosensitizing agent aminolevulinic acid (Levulan Kerastick) followed by blue light exposure was approved by the U.S. Food and Drug Administration (FDA) in 1999 for the treatment of nonhyperkeratotic lesions on the face and scalp. The protocol specifies a 14- to 18-hour incubation period between application of aminolevulinic acid and light exposure; however, a subsequent study has demonstrated the effectiveness of shorter incubation periods.23 Another protocol using the photosensitizing agent methyl aminolevulinate (Metvixia; not yet available in the United States) followed by red light exposure was approved by the FDA in 2004. This protocol specifies a three-hour incubation period.

Photodynamic therapy is well tolerated, has excellent cosmetic results, and has reported cure rates between 69 and 93 percent.16,21,24 Potential adverse effects include initial erythema; edema; a burning sensation; pain; and crusting followed by hypo- or hyperpigmentation, ulceration, or scaling.16,21

TOPICAL THERAPIES

Several topical therapies are available for the treatment of actinic keratoses, including various fluorouracil formulations, imiquimod 5% cream (Aldara), and diclofenac 3% gel (Solaraze). Although other topical agents (e.g., colchicine [topical formulation not available in the United States], tretinoin [Retin-A]) are used, there are no comparative phase III studies of these agents.25 Topical therapies are useful for patients with more than 15 actinic keratoses. The anatomic location of the lesions impacts the response time to topical treatments. Actinic keratoses on the face respond the quickest (more quickly than those on the scalp), whereas lesions on the arms usually take the longest to respond.26 After topical treatment, actinic keratoses may reoccur on the treated area.26,27

Fluorouracil

Topical fluorouracil is an established treatment for actinic keratoses and is the standard to which other topical treatments are compared. Fluorouracil cream is available in 5% (Efudex), 1% (Fluoroplex), and 0.5% (Carac) formulations.

Fluorouracil 5% cream is administered twice daily for two to four weeks. The application is associated with local irritation presenting as dryness, erythema, erosion, pain, or edema. Facial irritation and disfigurement associated with fluorouracil 5% cream makes the therapy undesirable to many patients. Studies have evaluated whether intermittent “pulse” applications decrease the adverse effects. However, these studies had small sample sizes and produced inconclusive results.28,29

Studies report similar effectiveness among fluorouracil formulations, although the 0.5% cream, which uses a microspore delivery system, causes less-severe adverse effects.30,31 However, studies comparing fluorouracil formulations are limited and include a small number of participants.

Fluorouracil 0.5% cream can be used as a neoadjuvant therapy before cryosurgery. A one-week course of fluorouracil 0.5% has been shown to reduce the number of lesions before cryosurgery and to decrease the risk of reoccurrence.32

Imiquimod

Imiquimod 5% cream is also approved for treatment of actinic keratoses. Imiquimod is applied once daily, two or three days a week, for 16 weeks. Several randomized, double-blind, vehicle-controlled trials showed that imiquimod 5% cream produced a complete response in 45 to 57 percent of patients and a partial response (i.e., 75 percent reduction in actinic keratoses) in 59 to 72 percent of patients.3335 One study showed that in the imiquimod treatment group, 20 percent of participants developed new lesions and none developed squamous cell carcinoma after 24 months of follow-up.27 By comparison, in the vehicle group, 90 percent of participants developed new lesions and one developed squamous cell carcinoma after one year of follow-up.27

Local reactions (e.g., erythema, scabbing or crusting, erosions or ulceration) are common with topical imiquimod therapy. Topical imiquimod also has been reported to produce systemic adverse effects, including fatigue, flu-like symptoms, and angioedema.36,37

Diclofenac

A randomized, double-blind, vehicle-controlled study compared topical diclofenac 3% in hyaluronan 2.5% gel with a hyaluronan 2.5% vehicle.38 Participants applied the treatments twice daily for 90 days, with follow-up 30 days after the end of treatment. Approximately 50 percent of participants in the treatment group had complete resolution compared with 20 percent in the vehicle group.38

Adverse effects associated with diclofenac 3% in hyaluronan 2.5% gel include pruritus, dry skin, application site reactions, rash, and erythema. Table 1 presents results from trials that evaluated the effectiveness of imiquimod and diclofenac in the treatment of actinic keratoses.3335,38

Table 1

Trials of Topical Treatments for Actinic Keratoses

Trials* Treatment regimen No. of participants Complete response (%) Partial response(%)

Diclofenac 3% (Solaraze) in hyaluronan 2.5% gel

Wolf, et al., 200138

Twice daily for 90 days

120

Treatment: 47.0

Vehicle: 19.0

Imiquimod 5% cream (Aldara)

Korman, et al., 200535

Once daily, three times per week, for 16 weeks

492

Treatment: 48.3

Treatment: 64.0

Vehicle: 7.2

Vehicle: 13.6

Lebwohl, et al., 200433

Once daily, two times per week, for 16 weeks

436

Treatment: 45.1

Treatment: 59.1

Vehicle: 3.2

Vehicle: 11.8

(95% CI, 34.9 to 49)‡

(95% CI, 39.5 to 55.1)‡

Szeimies, et al., 200434

Once daily, three times per week, for 16 weeks

286

Treatment: 57.1

Treatment: 72.1

Vehicle: 2.2

Vehicle: 4.3


CI = confidence interval.

*—Randomized, double-blind, vehicle-controlled, phase III trials.

†—75 percent reduction in actinic keratoses.

‡—CIs are for the treatment group minus the vehicle group.

Information from references 33 through 35 and 38.

Table 1   Trials of Topical Treatments for Actinic Keratoses

View Table

Table 1

Trials of Topical Treatments for Actinic Keratoses

Trials* Treatment regimen No. of participants Complete response (%) Partial response(%)

Diclofenac 3% (Solaraze) in hyaluronan 2.5% gel

Wolf, et al., 200138

Twice daily for 90 days

120

Treatment: 47.0

Vehicle: 19.0

Imiquimod 5% cream (Aldara)

Korman, et al., 200535

Once daily, three times per week, for 16 weeks

492

Treatment: 48.3

Treatment: 64.0

Vehicle: 7.2

Vehicle: 13.6

Lebwohl, et al., 200433

Once daily, two times per week, for 16 weeks

436

Treatment: 45.1

Treatment: 59.1

Vehicle: 3.2

Vehicle: 11.8

(95% CI, 34.9 to 49)‡

(95% CI, 39.5 to 55.1)‡

Szeimies, et al., 200434

Once daily, three times per week, for 16 weeks

286

Treatment: 57.1

Treatment: 72.1

Vehicle: 2.2

Vehicle: 4.3


CI = confidence interval.

*—Randomized, double-blind, vehicle-controlled, phase III trials.

†—75 percent reduction in actinic keratoses.

‡—CIs are for the treatment group minus the vehicle group.

Information from references 33 through 35 and 38.

Chemical peels

Facial peels using Jessner's solution (i.e., resorcinol, lactic acid, and salicylic acid in ethanol) and trichloroacetic acid 35% (Tri-Chlor) are comparable with fluorouracil in reducing actinic keratoses and reccurrence.39 Patients may prefer a chemical peel over fluorouracil because of the convenience of a single application.

The Authors

WILLIAM J. MCINTYRE, PharmD, is director of the University of Arkansas for Medical Sciences (UAMS) Area Health Education Center Southwest, Texarkana, and is an associate professor in the College of Pharmacy at UAMS. Dr. McIntyre received his pharmacy degree from Wayne State University, Detroit, Mich. He completed a clinical pharmacy residency at the University of Kentucky Chandler Medical Center, Lexington, and a cancer immunology fellowship at the University of Texas Health Science Center at San Antonio.

MICHAEL R. DOWNS, MD, is associate director of the UAMS Area Health Education Center Southwest Family Medicine Residency Program. Dr. Downs received his medical degree from UAMS, Little Rock, and completed a family medicine residency at the University of Oklahoma Tulsa Medical College.

SONDRA A. BEDWELL, RN, MNSc, FNP-C, is a family nurse practitioner in the faculty clinic and a clinical instructor in the graduate nursing program at UAMS Area Health Education Center Southwest. She received her bachelor's degree in nursing from Murray State University, Murray, Ky., and her bachelor's degree in biology from Bethel College, McKenzie, Tenn. She received her master's degree in nursing from UAMS.

Address correspondence to William J. McIntyre, PharmD, University of Arkansas for Medical Sciences Area Health Education Center Southwest, 300 E. 6th St., Texarkana, AR 71854 (e-mail: wjmcintyre@uams.edu).Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

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2. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol. 2000;42(1 pt 2):4–7.

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5. Drake LA, Ceilley RI, Cornelison RL, Dobes WL, Dorner W, Goltz RW, et al. Guidelines of care for actinic keratoses. Committee on Guidelines of Care. J Am Acad Dermatol. 1995;32:95–8.

6. Holman CD, Armstrong BK, Evans PR, Lumsden GJ, Dallimore KJ, Meehan CJ, et al. Relationship of solar keratosis and history of skin cancer to objective measures of actinic skin damage. Br J Dermatol. 1984;110:129–38.

7. Engel A, Johnson ML, Haynes SG. Health effects of sunlight exposure in the United States. Results from the first National Health and Nutrition Examination Survey, 1971–1974. Arch Dermatol. 1988;124:72–9.

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9. Guenthner ST, Hurwitz RM, Buckel LJ, Gray HR. Cutaneous squamous cell carcinomas consistently show histologic evidence of in situ changes: a clinicopathologic correlation. J Am Acad Dermatol. 1999;41(3 pt 1):443–8.

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13. Moller R, Reymann F, Hou-Jensen K. Metastases in dermatological patients with squamous cell carcinoma. Arch Dermatol. 1979;115:703–5.

14. Lund HZ. How often does squamous cell carcinoma of the skin metastasize? Arch Dermatol. 1965;92:635–7.

15. Dinehart SM, Nelson-Adesokan P, Cockerell C, Russell S, Brown R. Metastatic cutaneous squamous cell carcinoma derived from actinic keratosis. Cancer. 1997;79:920–3.

16. Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, Calzavara-Pinton PG, Zane C, et al. Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: a prospective, randomized study. J Am Acad Dermatol. 2002;47:258–62.

17. Lubritz RR, Smolewski SA. Cryosurgery cure rate of actinic keratoses. J Am Acad Dermatol. 1982;7:631–2.

18. Thai KE, Fergin P, Freeman M, Vinciullo C, Francis D, Spelman L, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol. 2004;43:687–92.

19. Hocutt JE Jr. Skin cryosurgery for the family physician. Am Fam Physician. 1993;48:445–52,455–6.

20. Freeman RG, Knox JM, Heaton CL. The treatment of skin cancer. A statistical study of 1,341 skin tumors comparing results obtained with irradiation, surgery, and curettage followed by electrodesiccation. Cancer. 1964;17:535–8.

21. Tarstedt M, Rosdahl I, Berne B, Svanberg K, Wennberg AM. A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)–PDT in actinic keratosis of the face and scalp. Acta Derm Venereol. 2005;85:424–8.

22. American Society for Dermatologic Surgery. Topical photodynamic therapy (PDT). Accessed April 9, 2007, at: http://www.asds-net.org/Media/PositionStatements/technology-photodynamictherapy.html.

23. Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest BA. A trial of short incubation, broad-area photodynamic therapy for facial actinic keratoses and diffuse photodamage. Arch Dermatol. 2004;140:33–40.

24. Radakovic-Fijan S, Blecha-Thalhammer U, Kittler H, Honigsmann H, Tanew A. Efficacy of 3 different light doses in the treatment of actinic keratosis with 5–aminolevulinic acid photodynamic therapy: a randomized, observer-blinded, intrapatient, comparison study. J Am Acad Dermatol. 2005;53:823–7.

25. Tutrone WD, Saini R, Caglar S, Weinberg JM, Crespo J. Topical therapy for actinic keratoses, II: diclofenac, colchicine, and retinoids. Cutis. 2003;71:373–9.

26. Simmonds WL. Topical management of actinic keratoses with 5-fluorouracil: results of a 6-year follow-up study. Cutis. 1972;10:737–41.

27. Stockfleth E, Christophers E, Benninghoff B, Sterry W. Low incidence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch Dermatol. 2004;140:1542.

28. Pearlman DL. Weekly pulse dosing: effective and comfortable topical 5-fluorouracil treatment of multiple facial actinic keratoses. J Am Acad Dermatol. 1991;25:665–7.

29. Epstein E. Does intermittent “pulse” topical 5-fluorouracil therapy allow destruction of actinic keratoses without significant inflammation? J Am Acad Dermatol. 1998;38:77–80.

30. Simmonds WL. Double-blind investigation comparing a 1%-vs-5% 5-flurouracil topical cream in patients with multiple actinic keratoses. Cutis. 1973;12:615–7.

31. Loven K, Stein L, Furst K, Levy S. Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther. 2002;24:990–1000.

32. Jorizzo J, Weiss J, Furst K, VandePol C, Levy SF. Effect of a 1-week treatment with 0.5% topical fluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized, vehicle-controlled clinical trial. Arch Dermatol. 2004;140:813–6.

33. Lebwohl M, Dinehart S, Whiting D, Lee PK, Tawfik N, Jorizzo J, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol. 2004;50:714–21.

34. Szeimies RM, Gerritsen MJ, Gupta G, Ortonne JP, Serresi S, Bichel J, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol. 2004;51:547–55.

35. Korman N, Moy R, Ling M, Matheson R, Smith S, McKane S, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol. 2005;141:467–73.

36. Systemic reactions to imiquimod (Aldara). Med Lett Drugs Ther. 2004;46:92.

37. Barton JC. Angioedema associated with imiquimod. J Am Acad Dermatol. 2004;51:477–8.

38. Wolf JE Jr, Talyor JR, Tschen E, Kang S. Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol. 2001;40:709–13.

39. Lawrence N, Cox SE, Cockerell CJ, Freeman RG, Cruz PD Jr. A comparison of the efficacy and safety of Jessner's solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Arch Dermatol. 1995;131:176–81.

This is one in a series of “Clinical Pharmacology” articles coordinated by Allen F. Shaughnessy, PharmD, Tufts University Family Medicine Residency Program, Malden, Mass.


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