Aim

To provide a summary of the efficacy and safety of topical comparator agents indicated for the treatment of AK.

Summary of Study Characteristics

Gupta et al. (2012)²¹ reported on a systematic review of numerous treatments for AK. This summary of the findings of the systematic review is specific to 5-FU 5% and imiquimod (5%, 3.75%, and 2.5%). The systematic review²¹ included 20 RCTs published between 2002 and 2010 that compared imiquimod (5%, 3.75%, and 2.5%) with placebo (18 studies) and imiquimod 5% with 5-FU 5% (two studies). Of the 18 studies comparing imiquimod with placebo, 15 used a 5% dose of imiquimod, 3 included a dose of 3.75%, and 2 included a dose of 2.5%. Three of the 15 studies comparing imiquimod 5% with placebo, two of which included an intra-individual design wherein patients applied imiquimod to lesions on one side of the body and vehicle cream to the other side, and one which included only immunosuppressed participants (organ transplant recipients), are not discussed, given that they were excluded from the pooled analyses and did not measure primary outcomes. There were no studies which compared 5-FU 5% with placebo. The participant characteristics in the included trials were generally similar. All studies included adult participants, with the majority being males with mean ages between 60 and 70 years.

Twelve studies comparing imiquimod 5% with placebo targeted the face, scalp, trunk, and extremities, with the number of doses per week ranging from two to seven. The duration of treatment ranged from 3 to 16 weeks and the total number of doses ranged from 9 to 56. The time of assessment ranged from immediately following treatment to eight weeks after the end of treatment. Proportion of patients achieving complete clearance and withdrawal due to adverse events were assessed in these studies (Table 39).

Table 39

Summary of Included Study Characteristics.

Three studies comparing imiquimod 3.75% with placebo targeted the face or scalp with all studies using seven doses per week. The duration of treatment ranged from four to six weeks and the total number of doses ranged from 28 to 42. The time of assessment ranged from 8 to 20 weeks after end of treatment. Proportion of patients achieving complete clearance and per cent mean reduction in lesion counts were assessed in these studies. Withdrawal due to adverse events was only assessed in two of the three studies (Table 39). Two of the three studies also compared imiquimod 2.5% with placebo.

Two trials comparing imiquimod 5% with 5-FU 5% targeted the head, neck, face, or scalp. The two trials used different dosing regimens which are summarized in Table 39. Assessments for both treatments were performed eight weeks after end of treatment. The proportion of patients achieving complete clearance, and withdrawal due to adverse events was assessed in both studies, while the mean per cent reduction in lesion count was reported for one of the two studies.

Summary of Findings

Gupta et al. (2012)²¹ reported that imiquimod 5% was favoured over placebo for complete clearance of AK based on pooled results from nine RCTs (n = 1,871, risk ratio [RR] 7.70 95%CI, 4.63 to 12.79) (Table 40). Complete clearance rates ranged from 5% to 84 % among the imiquimod 5% groups and 0% to 10% among the placebo groups. In eight RCTs, withdrawal due to adverse events was significantly higher in the 5% imiquimod group when compared with placebo (n = 2,290, RR 2.59, 95% CI, 1.59 to 4.23). The proportion of individuals who withdrew from the study due to adverse events ranged from 1.6% to 18.3% among the imiquimod 5% groups and 0% to 4% among the placebo groups.

Table 40

Summary of Pooled Analyses from Gupta et al. (2012).

Imiquimod 3.75% was favoured over placebo for complete clearance of AK (Table 40). Three RCTs provided pooled data for complete clearance (n = 730, RR 6.45, 95% CI, 3.87 to 10.73). Complete clearance rates ranged from 34.0% to 35.6% among the imiquimod 3.75% groups and 4.9% to 6.3% among the placebo groups. In two RCTs (n = 483), the difference in withdrawal due to adverse events was not statistically significantly different between imiquimod 3.75% and placebo based on pooled data.

Imiquimod 2.5% was favoured over placebo for complete clearance of AK (Table 40). Two RCTs provided pooled data for complete clearance (n = 486, RR 4.49, 95% CI, 2.40 to 8.39). Complete clearance rates ranged from 25.0% to 30.6% among the imiquimod 2.5% groups and 6.1% to 6.3% among the placebo groups. The incidence of withdrawal due to adverse events did not differ statistically between treatments.

Results of the two trials comparing imiquimod 5% with 5-FU 5% for complete clearance were not pooled due to the high level of heterogeneity between the trials (I² statistic = 93%). Variability in the dosing regimens employed in the two trials may partially explain the considerable disparity in results, wherein one trial reported statistical significance favouring 5-FU 5% over imiquimod 5% for complete clearance (n = 39, RR 0.31, 95% CI, 0.14 to 0.67) and the other trial reported no statistically significant between-treatment difference.

Critical Appraisal of Systematic Review

We assessed the systematic review methods used by Gupta et al. using the AMSTAR instrument. The systematic review included a comprehensive literature search, and study selection and data extraction were performed by two independent reviewers. A list of included and excluded studies was provided and the scientific quality of the included studies was assessed and documented. The systematic review was limited by the heterogeneity and low methodological quality of the included studies. Several studies did not distinguish between the physical locations of the AK lesion on the body. The authors of the systematic review reported the possibility of performance, detection, attrition, and reporting biases in numerous studies that compared imiquimod with placebo and 5-FU. Results should therefore be interpreted with caution.

Complete clearance rates and withdrawals due to adverse events for the imiquimod 5% studies varied, and were likely reflective of the heterogeneity of the dosing regimens, assessment periods, and treatment locations. The majority of trials assessing complete clearance of AK lesions using imiquimod 5% used two or three doses per week, typically over 16 weeks or less, targeted the face or bald scalp, and participants were assessed eight weeks after the end of treatment. Two studies that demonstrated different results were Gebauer et al. (2009)³⁷ and Stockfleth et al. (2002.)⁴²

Compared with the other studies, Gebauer et al. (2009)³⁷ reported lower clearance rates among both groups and more withdrawals due to adverse events among the imiquimod 5% group. Gebauer et al. (2009)³⁷ included four groups receiving two, three, five, and seven doses of imiquimod 5% per week over eight weeks and targeted the dorsal of one or both forearms and hands. The study had an overall low risk of bias. Potential sources of bias included uncertainty regarding allocation concealment, and although the study was double-blinded for the intervention versus control, it was not blinded for the frequency of application. Imiquimod appeared to be most effective in Stockfleth et al. (2002),⁴² though the study included a small sample size (n = 36) with patients assessed immediately after the 12-week treatment period, and included lesions on the head, neck, forearms, and hands. The study had an overall low risk of bias though there was insufficient detail regarding the method used to generate the allocation sequence.

Only three studies^39,40 were consistent with the Health Canada recommended dosing regimen of imiquimod 5% (twice weekly for 16 weeks).²² Two studies^47,48 were consistent with the Health Canada recommended dosing regimen of imiquimod 3.75% and 2.5% (once daily for two treatment cycles of two weeks each, separated by a two-week no-treatment period).²³ Only Tanghetti et al. (2007)⁵⁰ followed the Health Canada recommended dosing regimens for both imiquimod 5% and 5-FU 5%. Since few studies were consistent with Health Canada dosing regimens, the generalizability of these results in Canada is uncertain.

Conclusions

A recent systematic review of treatments for AK by Gupta et al. (2012)²¹ reported that, compared with placebo, imiquimod (5%, 3.75%, and 2.5%) produced a statistically significantly greater proportion of patients achieving complete clearance. Withdrawals due to adverse events were more common with a higher dose of imiquimod (5%) when compared with placebo, while there was no statistically significant difference in withdrawal due to adverse events when lower doses (3.75% and 2.5%) of imiquimod were compared with placebo. There is insufficient evidence to support the superiority of 5-FU over imiquimod for the treatment of AK given the conflicting results from two small trials. The systematic review identified no RCTs comparing 5-FU or imiquimod with ingenol mebutate, and given the between-trial heterogeneity, any comparisons between treatments that have not been directly compared should be made with caution.