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Imiquimod 5% Cream for the Treatment of Actinic Keratoses

N. Somani, MD and J. K. Rivers, MD, FRCPC
Division of Dermatology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada

ABSTRACT

Actinic keratoses (AKs) are premalignant inflammatory skin lesions with the potential to transform into squamous cell carcinoma (SCC). There are several treatment options available for patients presenting with multiple AKs. Imiquimod is believed to stimulate and enhance host immune responses locally against skin tumors and viral infections. Five clinical studies to date have demonstrated its safety and efficacy in the treatment of actinic keratoses. Long-term follow-up studies examining recurrence rates are limited.
Key Words: actinic keratosis, squamous cell carcinoma, immune response modifier

Imiquimod (Aldara™, 3M) is an immune response modifier that acts via stimulation of toll-like receptor 7 (TLR-7) on plasmacytoid and myeloid dendritic cells.1 TLR-7 is part of a family of 11 TLRs that are important in the innate immune system's recognition of various microbial antigens. Stimulation of TLR-7 most notably results in dissociation of nuclear factor kB (NFkB) away from its inhibitor, thereby freeing it to diffuse into the nucleus and transcribe genes for various cytokines including tumor necrosis factor a (TNFa), interferon g (IFNg), interferon a (IFNa), and interleukin-12 (IL-12), among others (see Figure 1). These cytokines upregulate cell mediated Th1 responses that have antitumor and antiviral effects and downregulate Th2 (humoral) responses. Imiquimod may also directly affect cell death through various pathways including via IFNg modulation of the p53 apoptotic pathway. Although initially licensed for the treatment of genital warts, imiquimod 5% cream has demonstrated therapeutic efficacy in a variety of dermatologic conditions and has recently been given approval by both the US FDA and Health Canada for the treatment of multiple AKs.

Actinic Keratoses

AKs are relatively common premalignant inflammatory skin lesions. The risk of malignant transformation of an average AK into a SCC in 1 year is 0.0075%.2 However, over a 10-year period, a person with an average of 8 AKs has a 6%-10% chance of developing an SCC.3 Treatment modalities employed include cryotherapy, topical fluorouracil (5-FU), photodynamic therapy (PDT), topical 3% diclofenac in 2.5% hyaluronic acid, retinoids, curettage, surgical excision, laser, and chemical peels/resurfacing procedures.

Imiquimod stimulation of TLR-7 results

Figure 1: Imiquimod stimulation of TLR-7 results in activation of IKK, which phosphorylates IęB. Unphosphorylated IkB keeps NFkB inactive. Phosphorylated IkB is ubiquitinated and degraded, freeing NFkB to move into the nucleus. NFkB acts as a transcription factor for genes encoding various cytokines.

IKK = inhibitor IkB kinase; IkB = inhibitor of NFkB;
NFkB = nuclear factor kB
Reprinted with permission from A-K Somani, MD, PhD.

Clinical Trials

In a randomized, double-blind, vehicle-controlled study, imiquimod 5% cream or vehicle was applied to AKs three times weekly for a maximum of 12 weeks.4 Three to 10 lesions from the scalp, forehead, dorsal forearm, neck, or dorsal hand, in an area not exceeding 20cm2, could be selected. At 2 weeks post-treatment, 21/25 (84%) patients were clinically cleared and 2/25 (8%) were partially cleared. No response was seen in the 11 subjects in the vehicle treated group (p< 0.001). Within the treatment group, clearance was 100% (15/15) in patients who required reduction to once or twice weekly therapy because of a brisk response to imiquimod. In those who were able to continue therapy at a frequency of three times weekly for 12 weeks, the clearance rate was 60% (6/10). All patients experienced local adverse effects ranging from mild to severe erythema, edema, erosions, vesicles, flaking and scabbing. One patient in the treatment group required a rest period of 10 days. All patients completed the 12-week treatment course. At the 1-year follow-up there was a 10% (2/25) recurrence rate in the treatment group.

In another clinical trial, 22 patients received imiquimod 5% cream three times weekly for 8 weeks (or until clearance) to one affected side of the body (either face, arms, or legs) and vehicle to the other side.5 Application sites were randomized. Seventy-eight percent of patients (17/22) completed the study (8 weeks of treatment and 8 weeks of post-treatment observation). Among these 17 patients, the mean number of lesions decreased from 10.1 to 6.2 versus 8.1 to 7.6 for the vehicle-treated group at 8 weeks post-treatment. This reached statistical significance (p< 0.005). Nine patients (53%) required one to two rest periods of 2 weeks' duration for local cutaneous reactions. Local side-effects were experienced by 14 patients (82%). A third study examined the efficacy of cyclical imiquimod therapy.6 This was an open-label trial of 25 patients with 5-20 discrete AKs within one cosmetic unit: the scalp, the forehead and temples, or the cheeks. This contrasts with other studies, which have included the neck, arms, hands, and legs. Imiquimod was applied to the entire treatment area ("field treatment") three times weekly for 4 weeks followed by a 4-week rest period. The cycle was repeated a maximum of three times if needed. Of the 25 patients with 33 total cosmetic units, 20 patients with 30 cosmetic units completed treatment. In the intention-to-treat analysis (ITT) 82% total clearance was achieved after three treatment cycles. Four patients had severe reactions that required early rest periods at 2-3 weeks of treatment. Of note, subclinical AKs exposed to imiquimod became evident in the treatment field. Furthermore, AK clearance continued during the rest period when no imiquimod was administered.

Study

N

Treatment

Complete Response

Probability

Randomized double-blind
vehicle-controlled study4

25

t.i.w. for 12wks or until clear

84% (21/25) treatment group
vs. 0% (0/11) placebo

p<0.001

Clinical trial
Single side treated; other
side vehicle control5

22

t.i.w. for 8wks or until clear

Mean number lesions decreased
10.1 to 6.2 vs. 8.1 to 7.6 placebo

p<0.005

Open-label studies6

25 pts with
33 CUs

t.i.w. for 4wks
on/4wks off
Max 3 cycles

ITT 82% (27/33)

Not reported

Phase III randomized,
multicenter, double-blind,
vehicle-controlled study7

436

Once daily b.i.w.
for 16 weeks

45.1% (97/215) treatment group
vs. 3.2% (7/221) placebo

p<0.001

Phase III randomized,
multicenter, double-blind,
vehicle-controlled study8

286

Once daily t.i.w.
for 16 weeks

57.1% (84/147) treatment group
vs. 2.2% (3/139) placebo

P<0.001

Table 1: Clinical trials results for imiquimod 5% cream.
CU = cosmetic units, each containing 5-20 discrete AKs
CR = complete response
ITT = intention-to-treat analysis



Medication

Medication

Complete Response

Imiquimod

Once daily b.i.w. or t.i.w. for 16wks 7,8
t.i.w. for 4wks cyclical therapy for 3 cycles
total 6

45-57% (p<0.001)
82% (p<0.001)

Photodynamic therapy

2 treatment sessions in 12 wks 26

73% (p<0.001)

73% (p<0.001)

4wks of treatment 17

52% (p<0.001)

5% 5-Fluorouracil

b.i.w.-q.i.w. for up to 16wks 16

88.6% (no p value)
Longer time to healing with
b.i.w. regimen

3% diclofenac in 2.5%
hyaluronic acid

30-90d of treatment b.i.d. 22,23

30-50% (p<0.05 and p<0.001)

Table 2: Response rates of various therapies used to treat actinic keratoses.



There have recently been large phase III, randomized, multicenter, double-blind, vehicle-controlled studies examining the use of imiquimod 5% cream for the treatment of AKs. The first of these published reports is a combination of two studies in which imiquimod 5% cream was applied once daily, 2 days per week for 16 weeks in 436 patients with 4-8 clinically diagnosed AKs on the face and scalp.7 Complete clearance, based on clinical assessment at 8 weeks post-treatment, was 45.1% (97/215) and 3.2% (7/221) for treatment and vehicle groups respectively (p< 0.001). Dosing days were a minimum of 3 days apart. Local skin reactions were common in both treatment and vehicle groups. However, these were more severe in the imiquimod treated group and resulted in 2 patients (1%) discontinuing treatment.

The second published study examined three times weekly imiquimod 5% cream applied to the face or balding scalp for 16 weeks in 286 patients with 5 to 9 clinically diagnosed and histologically confirmed AKs.8 Dosing days were the same nonconsecutive days every week. At 8 weeks post-treatment, the complete clinical clearance rate was 57.1% (84/147) with imiquimod versus 2.2% (3/139) in the vehicle treated group (p< 0.001). Adverse site reactions were reported by 46.3% (68/147) in the imiquimod group versus 11.5% (16/139) of patients using vehicle. Two patients using imiquimod (1%) discontinued therapy because of local side-effects.

Additional Treatment Options for AKs and Their Efficacy

There are no head-to-head trials comparing the efficacy of the various therapies used for the treatment of multiple actinic keratoses with that of imiquimod. Table 2 summarizes the response rates of various therapies that have been reported in the literature.

Cryotherapy is considered a standard treatment when patients present with a limited number of AKs (less than 15)9 or when there are multiple scattered lesions.10 The commonly used cryogen is liquid nitrogen (-195.8oC), which may be applied with techniques ranging from cotton-tip application to cryospray or cryoblast.11 The open-spray technique, with a freeze time of 5 to 10 seconds is effective.12 Prospective randomized controlled trials examining the efficacy of cryotherapy are lacking. Based on an observational study in which a 20 to 45 second total thaw time was used, a cure rate of 98.8% was achieved based on a recurrence rate of 12 out of 1,018 treated lesions in 70 patients followed for 1-8.5 years.10 Local side-effects such as blisters, scarring, and textural and pigmentary changes can rarely occur with cryotherapy.9 In patients with multiple AKs, the therapies listed below may be employed.

5-Fluorouracil (5-FU) is a structural analog of thymine that competes for enzymes with normal metabolites, such as uracil. Its cytotoxic effects are mediated by integration into RNA and inhibition of DNA synthesis by blockade of thymidylate synthetase.13 Typically the medication is applied twice daily for 3-4 weeks for facial lesions and 4-6 weeks on arms and hands until the lesions inflame and erode. In an effort to reduce the often intolerable side-effects of continuous therapy, the efficacy of pulse 5% 5-FU therapy has been examined in two studies. The earlier of these showed efficacy with once or twice weekly 5-FU applied for an average 6.7 weeks,14 while the other demonstrated little efficacy with intermittent therapy.15 Recently, a single-arm open-label study examined intermittent 5% 5-FU for up to 16 weeks in 53 patients with a total of 83 AKs on the face or scalp.16 All patients were initially treated 4 times per week (q.i.w.-twice daily on two consecutive days). After the first week, patients could switch to twice weekly application (b.i.w.-twice on a single day) if they experienced intolerable discomfort. Fifty patients (98%) with 79 lesions (95.1%) completed therapy. A total of 74.6% of lesions (59/79) were treated q.i.w., while 25.3% of lesions (20/70) were treated b.i.w. Complete healing was seen in 88.6% of lesions. Efficacy was not reduced as a result of less frequent application (complete clearance rates of 88.1% [52/59] and 90% [18/20] with q.i.w. and b.i.w. treatment respectively). Mean time to healing, however, did increase with decreased frequency of 5-FU application (7.4 weeks versus 10.2 weeks in the q.i.w. versus b.i.w. groups respectively).

One-half percent, 1%, and 2% concentrations of 5-FU have been developed. The one-half percent 5-FU cream was shown in two pooled, phase III studies of 384 patients to result in total AK clearance in 52.9% (45/85) of patients versus 1.6% (2/127) in the placebo group after 4 weeks of treatment (p< 0.001).17
In terms of comparative studies, chemical peel with Jessner's solution (resorcinol, lactic acid, and salicylic acid) combined with trichloroacetic acid and 5% 5-FU twice daily for 3 weeks were equal in efficacy.18 Photodynamic therapy has also been found to be equivalent in efficacy to 3 weeks of 5-FU treatment.19

Diclofenac is a nonsteroidal, anti-inflammatory drug that inhibits cyclo-oxygenase-2 resulting in reduced prostaglandin synthesis.20 Raised prostaglandins have been linked with sun damage and AKs.21 In a randomized, double-blind placebo-controlled study of 96 patients treated twice daily with 0.5 grams of topical 3% diclofenac in 2.5% hyaluronic acid for 90 days, 50% of patients showed complete resolution of all target lesions compared with 20% in the placebo group (p< 0.001).22 Another multicenter, double-blind, placebo-controlled study of 195 patients treated twice daily for 30 or 60 days with the same formulation of diclofenac achieved total lesion clearance of approximately 30% (in both 30- and 60-day treatment groups) versus approximately 10% in the placebo group.23 Adverse events included mild-to-moderate local pruritus, erythema and rash. The medication was well tolerated overall.24

Photodynamic therapy (PDT) employs aminolevulinic acid (ALA), a prodrug that is intracellularly metabolized to protoporphyrin IX, a photosensitizing molecule.25 When this is activated by exposure to light, free radicals and reactive oxygen species are generated.25 These are cytotoxic. A recent phase III, multicenter, investigator-blinded, randomized controlled trial examined the efficacy of ALA topical solution versus vehicle followed by blue light in the treatment of multiple AKs on the face and scalp in 243 patients.26 Following initial treatment, remaining target lesions were retreated at 8 weeks. Complete response rates achieved at 8 and 12 weeks were 66% (109/166) and 73% (109/149) respectively (p< 0.001). In the vehicle treated groups, complete responses were achieved in 11% (6/55) and 8% (4/52) at 8 and 12 weeks.

Moderate-to-severe stinging and burning were reported in 90% of patients during treatment, but this decreased after 24 hours. Additional side-effects of PDT include erythema and edema, which improve over 1-4 weeks. Pruritus, crusting, scaling, hyperpigmentation, and hypopigmentation may also be seen. This therapy is indicated for non-hyperkeratotic AKs.

Dosage and Adverse Effects

Imiquimod 5% cream is supplied in single-use sachets containing 250mg of the cream (12.5mg imiquimod).27 Each sachet can cover an area between 150 and 200cm2.28 Patients are instructed to apply imiquimod nightly, leave on for 6-10hrs, and then wash off. Hands should be washed after imiquimod application.

In general, imiquimod is well tolerated. Local cutaneous adverse effects are common, however, and include pruritus, burning, pain, erythema, erosions, edema, scabbing, induration, and ulceration.27
Erythema is the most common adverse reaction. In many of the above studies, dosing adjustments were required due to local reactions. Pretreatment counseling along with adequate follow-up will facilitate patient compliance with therapy. Serious systemic effects have not been reported.27
There are no known contraindications to treatment and no known drug interactions.27

Conclusions

Imiquimod is a reasonable treatment option in patients with multiple AKs. Health Canada has approved the treatment course at twice weekly for 16 weeks. Other treatment regimens can also be considered after the above treatment schedule.

A key component in the management of AKs remains the adoption of sun protective behaviors and sunscreens as a preventative strategy.29

References

  1. Hurwitz DJ, Pincus L, Kupper TS. Imiquimod: a topically applied link between innate and acquired immunity. Arch Dermatol 139(10):1347-50 (2003 Oct).
  2. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1(8589):795-7 (1988 Apr).
  3. Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic keratoses and the controversy over treatment. A patient-oriented perspective. Arch Dermatol 127(7):1029-31 (1991 Jul).
  4. Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 138(11):1498-502 (2002 Nov).
  5. 5Persaud AN, Shamuelova E, Sherer D, et al. Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis. J Am Acad Dermatol 47(4):553-6 (2002 Oct).
  6. Salasche SJ, Levine N, Morrison L. Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: an open-label trial. J Am Acad Dermatol 47(4):571-7 (2002 Oct).
  7. Lebwohl M, Dinehart S, Whiting D, 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 50(5):714-21 (2004 May).
  8. Szeimies R-M, Gerritsen MP, Gupta G, 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 51(4):547-55 (2004 Oct).
  9. Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol 42(1 Pt 2):25-8 (2000 Jan).
  10. Lubritz RR, Smolewski SA. Cryosurgery cure rate of actinic keratoses. J Am Acad Dermatol 7(5):631-219 (1982 Nov).
  11. Callaway SR, Ratz JL. Surgical pearl: cryoblast, a modified cryosurgical technique for thick lesions. J Am Acad Dermatol 51(3):458-9 (2004 Sep).
  12. Kuflik EG. Cryosurgery updated. J Am Acad Dermatol 31(6):925-44 (1994 Dec).
  13. Eaglstein WH, Weinstein GD, Frost P. Fluorouracil: mechanism of action in human skin and actinic keratoses. I. Effect on DNA synthesis in vivo. Arch Dermatol 101(2):132-9 (1970 Feb).
  14. Pearlman DL Weekly pulse dosing: effective and comfortable topical 5-fluorouracil treatment of multiple facial actinic keratoses. J Am Acad Dermatol 25(4):665-7 (1991 Oct).
  15. Epstein, E. Does intermittent "pulse" topical 5-fluorouracil therapy allow destruction of actinic keratoses without significant inflammation? J Am Acad Dermatol 38(1):77-80 (1998 Jan).
  16. Labandeira J, Pereiro M Jr, Valdes F, Toribio J. Intermittent topical 5-fluorouracil is effective without significant irritation in the treatment of actinic keratoses but prolongs treatment duration. Dermatol Surg 30(4 Pt 1):517-20 (2004 Apr).
  17. Gupta AK, Weiss JS, Jorizzo JL. 5-fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face and anterior scalp. Skin Therapy Lett 6(9):1-4. Review (2001 Jun).
  18. 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 131(2):176-81 (1995 Feb).
  19. Kurwa HA, Yong-Gee SA, Seed PT, Markey AC, Barlow RJ. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 41(3 Pt 1):414-8 (1999 Sep).
  20. Peters DC, Foster RH. Diclofenac/hyaluronic acid. Drugs Aging. 14(4):313-9 (1999 Apr).
  21. An KP, Athar M, Tang X, et al. Cyclooxygenase-2 expression in murine and human nonmelanoma skin cancers: implications for therapeutic approaches. Photochem Photobiol 76(1):73-80 (2002 Jul).
  22. Wolf JE Jr, Taylor JR, Tschen E, Kang S. Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 40(11):709-13 (2001 Nov).
  23. Rivers JK, Arlette J, Shear N, Guenther L, Carey W, Poulin Y. Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 146(1):94-100 (2002 Jan).
  24. Rivers JK. Topical 3% diclofenac in 2.5% hyaluronan gel for the treatment of actinic keratoses. Skin Therapy Lett 9(1):1-3 (2004 Jan).
  25. Gupta AK, Ryder JE. Photodynamic therapy and topical aminolevulinic acid: an overview. Am J Clin Dermatol 4(10):699-708 (2003).
  26. Piacquadio DJ, Chen DM, Farber HF, et al. Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials. Arch Dermatol 140(1):41-6 (2004 Jan).
  27. ALDARATM (imiquimod) CREAM, 5% Product Monograph 3M Pharmaceuticals (1997 May).
  28. Berman B, Ricotti CA Jr, Cazzaniga A, Davis SC. Determination of the area of skin capable of being covered by the application of 250 mg of 5% imiquimod cream. Dermatol Surg 30(5):784-6 (2004 May).
  29. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 329(16):1147-51 (1993 Oct).


  1. Table of Contents
  2. Imiquimod 5% Cream for the Treatment of Actinic Keratoses
  3. The Surgical Correction of Protuberant Ears
  4. Update on Drugs and Drug Warnings