Imiquimod cream for the treatment of adult patients with actinic keratosis

06 Mar 2009 Imiquimod cream for the treatment of adult patients with actinic keratosis

Introduction: This is an update to the February 2005 Therapeutics Initiative review of Imiquimod 5% cream (Aldara™) for the treatment actinic keratosis.

Drug

Imiquimod is an immune response modifier indicated for the treatment of clinically typical, non-hyperkeratotic, actinic keratosis on the face or balding scalp in adults. It is recommended to be applied once a day, twice weekly for a duration of 16 weeks (total of 32 doses).

Disease: Actinic Keratosis is the dysplasia of epidermis caused by prolonged ultraviolet damage. The risk of progression to skin cancer ranges from <1 to 16% per year (Glogau RG 2000, Marks R et al 1988). Diagnosis of actinic keratosis is usually through clinical history and physical examination and not often confirmed by histology.

Current standards of treatment: Cryosurgery and curettage are used for small areas with few lesions. Other treatment options include chemical peels, dermabrasion, laser therapy, excision and photodynamic therapy as well as retinoid therapy and intra lesional interferon. (Hadley G et al 2006)

Research question

In randomized controlled trials does imiquimod 5% cream provide a therapeutic advantage compared to no treatment, placebo (vehicle) or other standard therapy for the treatment of actinic keratosis on the face or balding scalp in adult patients?

Assessment principles

Included trials are double blind, single blind, or open label randomized controlled trials comparing 5% imiquimod cream to no treatment, placebo (vehicle) or other standard therapy in adult patients with actinic keratosis on the face or balding scalp. Therapeutic advantage will be assessed according to the following hierarchy of health outcomes – All cause mortality; non-fatal serious adverse events; disease specific morbidity (incidence of squamous cell carcinoma ); improvement in quality of life; patient and/or physician global degree of improvement in symptoms and/or signs; Lesion clearance rate of 100%; 75% clearance rate; severe adverse events, i.e. severe enough to require withdrawal of treatment, dose reduction or rest period; and other adverse events including cosmetic changes, including hypo pigmentation and scarring.

Search strategy and findings

MEDLINE database (1966-Nov 2008), EMBASE (1980- Nov 2008), and Cochrane database of systematic reviews and CENTRAL (issue 4, 2008) were searched to identify relevant trials. Thirteen RCTs met the inclusion criteria.

Results and overall summary:

There are no published RCTs that study the effect of imiquimod on the progression of AK lesions to squamous cell carcinoma.

Imiquimod vs active comparators:

Imiquimod vs 5FU

2 RCTs compared imiquimod to 5FU. One single blind RCT (Tanghetti et al 2007) in 39 patients (compared imiquimod 5% cream administered once daily, twice per week for 16 weeks [32 doses]. One open label RCT (Krawtchenko et al 2007) in 50 patients compared imiquimod 3 times per week for 4 weeks (1 course of treatment, 12 doses) to 8 weeks (2 courses of treatment, 24 doses) to 5% 5-FU cream administered twice daily for 2 to 4 weeks (28 to 56 doses). The duration of follow up was 24 weeks and 1 year after end of treatment, respectively.

No patient experienced a SAE until the end of follow up, 12 months after end of treatment. The only outcome that could be meta-analyzed was 100% clearance rate after 1 course of imiquimod therapy. 100% clearance at end of treatment was achieved significantly more with 5 FU than imiquimod (RR [95% CI] 4.44 [2.45, 8.03], p<0.0001) ARR= 69% NNT=1. However, 100% clearance rate as well as histologically confirmed clearance rates did not differ between 2 courses of treatment with imiquimod compared to treatment with 5 FU when measured at end of treatment.

Despite no significant difference in 100% clearance rate at end of treatment with 2 courses of imiquimod, at 12 month follow up, imiquimod was significantly better than 5 FU in sustained clearance of total treatment field (ARR =51%, NNT = 2); in global cosmetic outcome (ARR =77%, NNT = 1) and skin appearance as better improvement in skin quality (ARR = 25%, NNT = 4). Total adverse events were not reported.

Imiquimod vs cryotherapy

1 open label RCT (Krawtchenko et al 2007) compared imiquimod 3 times per week for 4 to 8 weeks (12 to 24 doses) to cryotherapy (20-40s per lesion, 1 or 2 courses) with duration of follow up of 12 months after end of treatment.

No patient experienced serious adverse event. Sqaumous cell carcinoma rate or QOL data was not reported. At end of treatment there was no significant difference in 100% clearance rate between the two groups (RR [95% CI] 1.24 [0.91, 1.70]) but imiquimod was significantly better than cryotherapy in histologically confirmed 100% clearance rates [ARR = 41.8%, NNT = 3]. At 12 months, imiquimod was significantly better than cryotherapy in sustained 100% clearance of total treatment field of AK lesions [ARR =80%, NNT=1]; in global cosmetic outcome (ARR =77%, NNT = 1) and skin appearance as better improvement in skin quality (ARR = 67, NNT = 2]. Total adverse events were not reported.

Imiquimod vs vehicle

Eleven randomized controlled trials compared imiquimod 5% cream to vehicle administered 2 to 3 times per week for 4 to 16 weeks with a post treatment follow up ranging from 2 to 8 weeks. Total doses of imiquimod administered varied from 9 to 96 doses. The most common primary outcome measure (9 of the 11 trials) was 100% clearance of actinic keratosis lesions (clinical or clinical and histological).

Serious adverse events were not significantly increased in the imiquimod group as compared to vehicle group RR with 95% CI = 0.93[0.59, 1.45]. Imiquimod [12 to 96 doses] was significantly better than vehicle at 100% clearance [ARR = 44%, NNT =2] and 75% clearance of AK lesions [ARR = 50%, NNT =2]. Meta-analysis of trials based on total doses administered showed that imiquimod applied once a day, 3 times per week for 4 weeks (12 doses) as compared to placebo was not significantly different in terms of the 100% clearance rate than longer term therapy over 16 weeks (32 or 48 doses) [NNT=2]. 32 doses is the recommended total dose of imiquimod according to the product monograph. Total adverse events were significantly increased in imiquimod group at 9, 12, 32 and 48 doses as compared to vehicle. Meta-analysis of total AE at all doses vs. vehicle showed a significant increase in adverse events [ARI = 18% and NNH =6]. Withdrawals due to adverse events were not significantly different.

Critical appraisal of included trials: None of the available trials were of sufficient duration to study the progression of actinic keratosis lesions to squamous cell carcinoma. Instead, all the included studies measured the recurrence rate of actinic keratosis lesions or cosmetic differences between lesions. The available trials did not use the same clinical criteria for actinic keratosis diagnosis. Skin biopsy used to confirm the clinical diagnosis of one lesion does not validate the accuracy of diagnosis of other actinic keratosis lesions included in a study. The complete clearance rate, which is the primary outcome measure of the available trials may or may not indicate a beneficial effect in terms of the subset of lesions that evolve into skin cancer. Histologically confirmed 100% clearance rates are lower than clinically determined 100% clearance rates. Systemic side effects of imiquimod compared to pharmacological and non-pharmacological treatment (such as cryotherapy) has not been reported. There is inadequate reporting of adverse events in the active comparator trial versus 5-fluorouracil and cryotherapy.

Conclusions

No RCTs studied the effectiveness of imiquimod as compared to placebo or other drugs on the progression of actinic keratosis lesions to squamous cell carcinoma in adult patients.
Two RCTs compared imiquimod 5% cream (12 to 32 doses) to 5-fluorouracil cream (28 to 56 doses). Although imiquimod did not differ significantly from 5 FU in 100% clearance rate at end of treatment, at 12 months imiquimod (24 doses) provided a therapeutic advantage over 5 FU (28 to 56 doses) in terms of sustained 100% clearance of actinic keratosis lesion in total treatment field (ARR =51%, NNT = 2); in global cosmetic outcome (ARR =77%, NNT = 1) and better improvement in skin quality (ARR = 25%, NNT = 4). Total adverse events were not reported.

One open label RCT compared imiquimod 3 times per week for 4 to 8 weeks (12 to 24 doses) to cryotherapy (20-40s per lesion, 1 or 2 courses) with duration of follow up of 12 months after end of treatment. At 12 months, imiquimod provided a therapeutic advantage over cryotherapy in histologically confirmed 100% clearance rates [ARR = 41.8%, NNT = 3]; sustained 100% clearance of actinic keratosis lesion in total treatment field [ARR =80%, NNT = 1]; in global cosmetic outcome (ARR =77%, NNT = 1) and better improvement in skin quality (ARR = 67, NNT = 2]. Total adverse events were not reported.

Eleven RCTs compared imiquimod 5% cream (9 to 96 doses) to vehicle with a post treatment follow up ranging from 2 to 8 weeks. Imiquimod provided a therapeutic advantage over vehicle in 100% clearance of AK lesions [44%, NNT =2] and 75% clearance rate [50%, NNT =2]. Imiquimod applied once a day, 3 times per week for 4 weeks (a total of 12 doses) as compared to vehicle was not significantly different in terms of the 100% clearance rate than longer term therapy over 16 weeks, 32 or 48 doses [NNT=2]. 32 doses is the recommended total dose of imiquimod according to the product monograph. Total adverse events, mainly skin rashes, were significantly increased in imiquimod group [ARI = 18% and NNH =6]. Withdrawals due to adverse events were not significantly different.

References

1. Alomar A et al. Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratosis on the head. British Journal of Dermatology 2007;157:133–141.
2. Canadian Pharmacist Association (CPS). E-Therapeutics online. http:// https://www.e-therapeutics.ca. 2008
3. Chen K, Yap LM, Marks R, Shumack S. Short-course therapy with imiquimod 5% cream for solar keratosis: A randomized controlled trial. Aust J Dermatol 2003; 44:250-255.
4. Drake LA et al. Guideline of care for actinic keratoses. J Am Acad Dermatol 1995;32:95-98.
5. Epstein E. Quantifying Actinic. Am J Clin Dermatol 2004; 5: 141- 44.
6. Glogau RG et al. The risk of progression to invasive disease. J Am Acad Dermatol 2000;42:S23-24.
7. Gupta AK, Inniss K, Wainwright R, Chow M, Cooper E. Interventions for actinic keratosis (Protocol for a Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.
8. Hadley G et al. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Investig Dermtol 2006;126:1251-1255.
9. Helfand M et al. Actinic Keratosis-final report. http://cms .hhs.gov/coverage/download/8b3-t3.pdf. 2001. Agency for healthcare research and quality. 11-6-2003.
10. Jorizzo J et al. Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratosis on the head. J Am Acad Dermatol 2007;57:265-8.
11. Korman N et al. Dosing With 5% Imiquimod Cream 3 Times per Week for the Treatment of Actinic Keratosis. Arch Dermatol 2005;141:467-473.
12. Krawtchenko N et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. British Journal of Dermatology 2007;157 (Suppl. 2):34–40.
13. 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.
14. Marks R et al. Malignant transformation of solar keratoses to sqaumous cell carcinoma. Lancet 1988;1:296-297.
15. Persaud AN, Shamuelova E, Sherer D, Lou W, Singer G, Cervera C, et al. Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis. J Am Acad Dermatol 2002; 47: 553-56.
16. Ooi T et al. Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial. British Journal of Dermatology 2006;154:72–78.
17. Stockfleth E, Meyer T, Benninghoff B, Salasche S, Papadopoulos L, Ulrich C, et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratosis. Arch Dermatol 2002; 138: 1498-502.
18. Szeimies R-M, Gerritsen M-J, Gupta G, Paul OJ, 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.
19. Tanghetti E et al. Comparison of 5% fluorouracil cream and 5% imiquimod cream in management of actinic keratoses on the face and scalp. Journal of drugs in dermatology;2007(6):144-147.
20. Torres A et al. Microarray analysis of aberrant gene expression in actinickeratosis: effect of the Toll-like receptor-7 agonist imiquimod. British Journal of Dermatology 2007;157:1132–1147.
21. Ulrich C et al. Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. British Journal of Dermatology 2007, 157 (Suppl. 2), 25–31.
22. Weinstock MA, Bingham SF, Cole GW, et al. Reliability of counting actinic keratosis before and after brief consensus discussion. Arch Dermatol 2001; 137: 1055-8.
23. Whited JD, Homer RD, Hall RP, et al. The influence of history on interobserver agreement for diagnosing actinic keratosis and malignant skin lesions. I Am Acad Dermatol 1995; 33: 603-7.