AK, actinic keratosis; ALA, 5-aminolevulinic acid; DFS, diclofenac sodium 3% gel; 5-FU, 5-fluorouracil; PDT, photodynamic therapy.
Effectiveness of 5-fluorouracil treatment for actinic keratosis – a systematic review of randomized controlled trials
Version of Record online: 9 APR 2009
© 2009 The International Society of Dermatology
International Journal of Dermatology
Volume 48, Issue 5, pages 453–463, May 2009
How to Cite
Askew, D. A., Mickan, S. M., Soyer, H. P. and Wilkinson, D. (2009), Effectiveness of 5-fluorouracil treatment for actinic keratosis – a systematic review of randomized controlled trials. International Journal of Dermatology, 48: 453–463. doi: 10.1111/j.1365-4632.2009.04045.x
- Issue online: 9 APR 2009
- Version of Record online: 9 APR 2009
Actinic keratosis (AK) lesions present as dry, rough, yellow–brown, scaly plaques which may become thickened and horny. Most AKs are caused by chronic exposure to ultraviolet (UV) radiation and are therefore most common in middle-aged and elderly fair-skinned individuals. Regions with a higher UV exposure show a higher prevalence, and the incidence rate increases with age.1 Around 15–25% of lesions resolve spontaneously over a 12-month period, and the risk of a single lesion progressing to an invasive squamous cell carcinoma (SCC) is in the range 0.25–20% per year.2,3 Opinion differs about the classification of AKs – some argue that they should be classified as in situ SCC because they are histopathologically indistinguishable from SCCs,3 whereas others argue that the classification of in situ SCC, although histopathologically correct, is liable to misinterpretation by consumers, leading to unnecessary and excessive concerns generated by a diagnosis of cancer and additional costs to already overburdened healthcare systems.4 Nevertheless, the inability to predict which AK lesions will transform into invasive SCCs means that the treatment of all AKs is indicated.
Topical 5-fluorouracil (5-FU) is a well-established treatment for AK. 5-FU is an antineoplastic antimetabolite, which interferes with the synthesis of DNA and RNA, provoking unbalanced cell growth and death. 5-FU enables field therapy for patients with multiple AKs, and may also promote the healing of subclinical lesions.5 Treatment is lengthy (about 4 weeks) and application site reactions, ranging from redness, soreness and weeping to shallow ulceration and crusting, are a consequence of treatment.
Despite the widespread use of 5-FU to treat AK, the evidence supporting its use has not been reviewed systematically or appraised critically, unlike that for imiquimod.6–8 We therefore reviewed systematically the published literature to address this gap, and to identify areas in which further research is needed.
In January 2008, the Medline (1966 to present) database (via PubMed) was searched for randomized controlled trials (RCTs) of treatment of AK with 5-FU. The EMBASE database and The Cochrane Central Register of Controlled Trials were also searched, as were the reference lists of the included studies.
Studies were included in this review if they reported RCTs on humans comparing the treatment of AK with 5-FU, placebo, or another active treatment, or investigated different 5-FU dosage regimens. Participants in the included studies all had clinical symptoms of AK – a histologic diagnosis was not required. Papers were excluded if they were not written in English or if they were case reports or observational studies.
Each included study was reviewed by two authors (DA and SM) and the following data were extracted (if available) and recorded: publication citation; details of the participants (number of participants in each treatment group, gender, age, and number and location of lesions); method of diagnosis of AK; details of the intervention regimen (dosing frequency, duration of treatment, assessment intervals, and length of follow-up); study design; number of patients achieving complete clearance of lesions; changes in the mean number of lesions; other outcome data; number of patients withdrawing from the study as a result of adverse events; and authors’ declared conflicts of interest, sponsorship, and acknowledgment of editorial freedom.
Assessment of risk of bias in the included studies and data analysis
Each study was evaluated for the following areas of potential bias: random sequence generation; allocation concealment; blinding during the study; objectiveness of outcome assessment; completeness of follow-up; use of intention-to-treat analysis; occasions of selective reporting; and objectiveness of outcome measures.9
Where possible, the weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated for studies reporting changes in the mean number of lesions per participant and mean lesion area per patient, and the odds ratios (OR) and 95% CIs for studies reporting the number of patients achieving 100% clearance.10 The use of different outcome measures in most trials precluded a pooled estimate of the treatment effect for each outcome measure across trials.
Description of studies
In all, 29 studies were identified through database and hand searching of reference lists. Of these, 16 were rejected (Fig. 1) and the remaining 13 RCTs were included.
One study compared 5% 5-FU with facial resurfacing with either carbon dioxide (CO2) laser or 30% trichloroacetic acid peel for the treatment of AK and the prevention of nonmelanoma skin cancer over 5 years.11 Only data relating to the treatment of AK lesions, measured 3 months after treatment, were included in this review. Another study compared the efficacy of a 1-week treatment with 0.5% 5-FU followed by cryotherapy on the remaining lesions at 4 weeks post-treatment with cryotherapy alone.12 A reduction in AK count was measured prior to cryotherapy, and only these data were included in this review. Table 1 presents details of the included studies, including the number and characteristics of the participants, treatment groups, assessment period, and main outcomes.
|Study||Participants||Diagnosis||Study design||Treatment groups||Assessment period (weeks)*||Main outcome measures|
|Bercovitch18||20 participants Multiple AKs on hands and forearms||Histologic||Bilateral (split hand and forearm)||Group 1: 5% 5-FU twice daily for 2–4 weeks Group 2: 5% 5-FU twice daily + tretinoin 0.05% once daily for 2–4 weeks||8||Mean number of AK lesions per patient: Group 1: 15.3 ± 6.9 (baseline) 4.2 ± 2.5 (week 12) Group 2: 15.7 ± 6.1 (baseline) 3.4 ± 2.6 (week 12)|
|Hantash et al.11||23 participants Multiple AKs on face or scalp||Clinical||Parallel groups||Group 1: 5% 5-FU twice daily for 3 weeks, n = 9 Group 2: full-face CO2 laser resurfacing, n = 8 Group 3: 30% trichloroacetic acid peel, n = 9||9||Mean number of AK lesions per patient: Group 1: 61.8 ± 22.4(baseline) 8.8 ± 6.3 (week 12) Group 2:78.0 ± 29.2(baseline) 5.5 ± 6.2 (week 12) Group 3: 83.7 ± 38.4(baseline) 7.7 ± 3.3 (week 12) Mean % decrease in AK lesions per patient: Group 1: 83.2% ± 12.5; Group 2: 92.0% ± 10.3; Group 3:89.0% ± 6.6 Patients achieving 100% clearance: Group 1: 2/9 (22.2%); Group 2: 3/8(37.5%); Group 3: 0/9 (0%)|
|Jorizzo et al.20||207 participants [80% male (166), 20% female (41)] ≥ 5 lesions (≥ 4 mm in diameter) on face or frontal scalp||Not stated||Parallel groups||Group 1: once daily 0.5% 5-FU for 1 week, n = 47 Group 2: once daily 0.5% 5-FU for 2 weeks, n = 46 Group 3: once daily 0.5% 5-FU for 4 weeks, n = 45 Group 4: once daily vehicle cream for 1, 2 or 4 weeks, n = 69||4||Mean % decrease in AK lesions per patient: Group 1: 69.5; Group 2: 86.1; Group 3: 91.7; Group 4: 21.6 Patients achieving 100% clearance: Group 1: 14.9%; Group 2: 37.0%; Group 3: 57.8%; Group 4: 0%|
|Jorizzo et al.12||144 participants Mean age, 62.6 years ≥ 5 lesions on face||Clinical||Parallel groups||Group 1: 0.5% 5-FU once daily for 1 week, n = 72 Group 2: vehicle cream once daily for 1 week, n = 72||3||Mean number of AK lesions per patient: Group 1: 13.7 ± 9.3 (baseline) 4.3 ± 3.8 (week 4) Group 2: 13.1 ± 7.6 (baseline) 9.1 ± 6.1 (week 4) Patients achieving 100% clearance: Group 1: 12/72 (17.0%); Group 2: 0/70|
|Jury et al.19||20 participants [95% male (19), 5% female (1)] Mean age, 73 years (range, 49–85 years) Median lesion count on face and scalp = 17.5||Clinical||Parallel groups||Group 1: 5% 5-FU twice daily for 3 weeks, n = 13 Group 2: 5% 5-FU once daily, one day per week, for 12 weeks, n = 7||40||Decrease in median lesion count: Group 1: 17.5 (baseline) 0 (week 52) Group 2: 17.5 (baseline) 3 (range, 1–6) (week 52)|
|Krawtchenko et al.14||75 participants [83% male (62), 17% female (13)] Mean age, 73 years (range, 57–88 years) 5–10 lesions in one 50 cm2 area at head, neck, or décolleté||Histologic||Parallel groups||Group 1: 5% 5-FU twice daily for 4 weeks, n = 24 Group 2: cryotherapy (liquid nitrogen spray) for 20–40 s per lesion. Repeated after 2 weeks if insufficient clearance, n = 25 Group 3: imiquimod three times weekly for 4 weeks, followed by 4 weeks of rest. Treatment cycle repeated if any lesions remained at end of rest period, n = 26||Group 1: 4Group 2: 6Group 3: 8||Patients achieving 100% clearance (clinical and histologic evaluation) at end of initial assessment period: Group 1: clinical 23/24 (96%); histologic 16/24 (67%) Group 2: clinical 17/25 (68%); histologic 8/25 (32%) Group 3: clinical 22/26 (85%); histologic 16/24 (67%) Sustained clearance of lesions in treatment field at 12 months: Group 1: 8/24 (33%) Group 2: 1/25 (4%) Group 3: 19/26 (73%)|
|Kurwa et al.17||17 participants [47% male (8), 53% female (9)] Age, 53–79 years Long history of AK on hands and forearms||Not stated||Bilateral (split hand)||Group 1: 5% 5-FU twice daily for 3 weeks, one hand, n = 17 Group 2: ALA PDT, 4 h application time, activated by red light (150 J/cm2), other hand, n = 17||23||Change in mean lesion area: Group 1: 1390 mm2 ± 1130(baseline) 297 mm2 ± 209 (70% reduction) Group 2: 1322 mm2 ± 1280(baseline) 291 mm2 ± 291 (73% reduction) Patients achieving 100% clearance: No patients in either group|
|Loven et al.5||21 participants [81% male (17), 19% female (4)] Mean age, 70.4 years (± 8.5) ≥ 6 lesions (three on each side of face, anterior bald scalp or forehead) Mean number of lesions: 10.9 on right side, 10.8 on left||Clinical||Bilateral (split face)||Group 1: 5% 5-FU twice daily for 4 weeks (or until patient unable to tolerate), n = 21 Group 2: 0.5% 5-FU once daily for 4 weeks (or until patient unable to tolerate), n = 21||4||Mean number of AK lesions per patient: Group 1: 10.3 (baseline) 4.2 (week 8) Group 2: 11.3 (baseline) 2.5 (week 8) Patients achieving 100% clearance: Group 1: 43%; Group 2: 43%|
|Ostertag et al.16||55 participants [92% male (50), 8% female (5)] Mean age, 72 years (range, 52–85 years) Mean lesion count on face or scalp = 15||Histologic||Parallel groups||Group 1: 5% 5-FU twice daily for 4–7 weeks, n = 27 Group 2: full-face laser resurfacing, n = 28||48||Mean number of AK lesions per patient: Group 1: 15.3 ± 4.9 (baseline) 2.9 (week 52) Group 2: 14.9 ± 5.4 (baseline) 0.5 (week 52) Mean % of lesions cleared per patient: Group 1: 76.6%; Group 2: 91.1%|
|Smith et al.22||36 participants [81% male (29), 19% female (7)] Mean age range, 58.9–64.3 years ≥ 4 nonhyperkeratotic lesions on face Mean number of lesions, 5.8–6.8||Not stated||Parallel groups||Group 1: 0.5% 5-FU once or twice daily for 4 weeks, n = 12 Group 2: ALA PDT, 1 h application time, activated by blue light for 1000 s. Repeated after 30 days, n = 12 Group 3: ALA PDT, 1 h application time, activated by 595 nm pulsed dye laser. Repeated after 30 days, n = 12||4||Patients achieving 100% clearance: Group 1: 6/12 (50%); Group 2: 6/12 (50%); Group 3: 1/12 (8%) Decrease in total number of lesions: Group 1: 79%; Group 2: 80%; Group 3: 60%|
|Smith et al.15||30 participants [77% male (23), 23% female (7)] ≥ 3 lesions on each side of face and/or scalp and relative symmetry of lesion distribution||Clinical||Bilateral (split face)||Group 1: 5% 5-FU twice daily for final 28 days of 90-day treatment period, n = 30 Group 2: DFS twice daily for 90 days, n = 30||4||Decrease in total number of lesions: Group 1: 98% clearance (124/126 resolved) Group 2: 89% clearance (111/125 resolved)|
|Tanghetti and Werschler13||39 participants ≥ 4 lesions in one 25 cm2 area on face, forehead, or scalp||Not stated||Parallel groups||Group 1: 5% 5-FU twice daily for 2–4 weeks, n = 20 Group 2: imiquimod twice weekly for 16 weeks, n = 19||8||Decrease in total number of lesions: Group 1: 93.8% clearance (606/646 resolved) Group 2: 65.9% clearance (323/490 resolved) Patients achieving 100% clearance: Group 1: 84% Group 2: 24%|
|Weiss et al.21||177 participants [86% male (152), 14% female (25)] Mean age, 63.1 years (range, 35–89 years) ≥ 5 lesions ≥ 4 mm on face or frontal scalp Mean number of lesions 12.8 ± 6.4||Clinical||Parallel groups||Group 1: 0.5% 5-FU once daily for 1 week, n = 38 Group 2: 0.5% 5-FU once daily for 2 weeks, n = 41 Group 3: 0.5% 5-FU once daily for 4 weeks, n = 40 Group 4: vehicle cream once daily for 1, 2 or 4 weeks, n = 58||4||Mean % decrease in AK lesions per patient: Group 1: 78.5%; Group 2: 83.6%; Group 3: 88.7%; Group 4: 34.4% Patients achieving 100% clearance: Group 1: 26.3%; Group 2: 19.5%; Group 3: 47.5%; Group 4: 3.4%|
Eight studies compared 5% 5-FU with other treatments – imiquimod,13,14 cryotherapy,14 diclofenac sodium 3% gel (DFS),15 facial resurfacing,11,16 photodynamic therapy (PDT),17 5% 5-FU augmented with tretinoin,18 and 0.5% 5-FU.5 One study compared different dosing regimens of 5% 5-FU (twice daily for 3 weeks vs. twice daily for 1 day per week for 12 weeks).19 Three studies compared 0.5% 5-FU with placebo,12,20,21 and one compared 0.5% 5-FU with 5-aminolevulinic acid (ALA) PDT, activated with either blue light or pulsed laser light22 (Table 1).
Several different outcome measures were used to determine the efficacy of treatment, including absolute and proportional changes in lesion counts per patient, changes in total lesion count, change in lesion area, tolerability, and patient preferences (Table 1). Nine studies reported the proportion of patients achieving 100% clinical clearance of the lesions.5,11–14,17,20–22
Duration of assessment
The duration of follow-up varied between the studies. As the complete healing of lesions treated with 5% 5-FU may not be evident for up to 2 months following the cessation of active treatment,23 8 weeks post-treatment was considered to be the minimum time period to ascertain short-term benefit. The assessment in seven studies was short, with outcomes being assessed 4 weeks after the cessation of treatment.5,11,13,14,19–21 Three studies assessed outcomes at around 8 weeks,11,13,18 and long-term assessment data were reported in four studies, at 6 months17 and 12 months14,16,19 post-treatment.
Reduction in mean or median number of lesions
Treatment with 5% 5-FU resulted in an average reduction of 79.5% (range, 59.2%–100%) in the mean number of lesions, from an average of 24.0 at baseline (range, 10.3–61.8) to 4.0 (range, 0–8.8) at follow-up.5,11,16,18,19 In comparison, treatment with 0.5% 5-FU resulted in an average reduction of 86.1% (range, 77.9%–91.7%) in the mean number of lesions, from an average of 13.9 lesions at baseline to 3.9 lesions at follow-up.20,21 The average number of lesions was reduced by 94.5% (range, 92.9–96.6%) when treated by laser resurfacing,11,16 and 28.0% (range, 21.6–34.4%) when treated with placebo12,20,21 (Table 1).
Of the eight studies that reported a reduction in the mean or median number of lesions per patient, only three provided sufficient data to enable assessment of the WMD.11,12,18 There was no difference in the WMD of 5% 5-FU compared with 5% 5-FU augmented with tretinoin (WMD, –0.8; 95% CI, –2.4, 0.8),18 resurfacing with CO2 laser (–3.3; –9.9, 3.3) or 30% trichloroacetic acid peel (–1.1, –6.0, 3.8).11 Treatment with 0.5% 5-FU for 1 week resulted in a significantly greater reduction in the mean number of lesions per patient than did placebo (4.8; 3.1, 6.5).12
Reduction in the total number of lesions
Treatment with 5% 5-FU cleared 93.8% (606/646) of lesions at 24 weeks,13 and 98.0% (124/126) of lesions at 4 weeks,15 compared with 65.9% (323/490) of lesions cleared with imiquimod13 and 89% (111/125) of lesions cleared with DFS15 (Table 1). The study comparing 0.5% 5-FU with ALA PDT, activated by either blue light or pulsed laser, reported clearance values of 79%, 80%, and 60% of lesions, respectively, but no raw data were reported.22
Patients achieving clearance of 100% of lesions
Across the studies, an average of 49.0% (range, 0%–96%) of patients treated with 5% 5-FU5,11,13,14,17 and 34.8% (14.9–57.8%) of patients treated with 0.5% 5-FU5,12,20–22 were reported as achieving clearance of 100% of lesions. In comparison, 100% clearance was reported by no patients treated with acid peel11 or ALA PDT activated with red light,17 in 0–4.3% of patients using placebo,12,20,21 in 37.5% (3/8) of patients treated with CO2 laser resurfacing,11 in 50% (6/12) of patients treated with ALA PDT activated by blue light,22 in an average of 54.5% (range, 24–85%) of patients treated with imiquimod,13,14 and in 68% of patients treated with cryotherapy.14
Only four papers provided sufficient data to calculate ORs and 95% CIs for this outcome measure (Table 2).11,12,14,22 Significantly larger numbers of patients achieved clearance of 100% of lesions when treated with 5% 5-FU compared with cryotherapy (OR, 10.8; 95% CI, 1.2, 94.9),14 and 0.5% 5-FU for 1 week compared with placebo (30.0; 1.7, 516.5)12 or ALA PDT activated by pulsed laser light (11.0; 1.1, 114.1).22
|5% 5-FU11||2/9||30% trichloroacetic acid peel||0/9||6.3||(0.3, 152.9)|
|5% 5-FU11||2/9||CO2 laser resurfacing||3/8||0.5||(0.06, 4.0)|
|5% 5-FU14||23/24||Cryotherapy||17/25||10.8||(1.2, 94.9)|
|5% 5-FU14||23/24||Imiquimod||22/26||4.2||(0.4, 40.4)|
|0.5% 5-FU (1 week of treatment)12||12/72||Placebo||0/72||30.0||(1.7, 516.5)|
|0.5% 5-FU22||6/12||ALA PDT (activated by blue light)||6/12||1.0||(0.2, 5.0)|
|0.5% 5-FU22||6/12||ALA PDT (activated by pulsed dye laser)||1/12||11.0||(1.1, 114.1)|
Sustained clearance of the treatment area at 12 months after the cessation of treatment was assessed in only one study, and was observed in 33% (8/24) of patients treated with 5% 5-FU, 4% (1/25) of patients treated with cryotherapy, and 73% (19/26) of patients treated with imiquimod.14
Treatment with 5-FU is associated with application site reactions, and most studies assessed the severity of these reactions, although the methods varied between studies making data synthesis difficult.5,12,13,15–17,20–22 Cosmetic outcome was assessed in only one study – at 3 months, there was no difference between the groups treated with 5% 5-FU, cryotherapy, or imiquimod; however, at 12 months, 4% of patients treated with 5% 5-FU or cryotherapy and 81% of patients treated with imiquimod showed an excellent cosmetic outcome (based on scarring, atrophy, and induration).14 This is a very large difference, but it is unclear whether investigators were blind to the treatment groups, introducing a high risk of bias in these results.
Only two studies assessed patient preferences for treatment.5,15 In the study comparing 0.5% and 5% 5-FU, 85% (17/20) of patients preferred 0.5% 5-FU, with the remaining three patients preferring 5% 5-FU.5 The study comparing DFS and 5% 5-FU reported that 79% of patients were very or completely satisfied with DFS, compared with 68% with this level of satisfaction with 5% 5-FU.14 The patients were not blind to the treatment in either of these studies, however, limiting the validity of this assessment. Overall, only three studies reported the number of patients withdrawing from the study as a result of adverse events: 1.9% (4/213) of patients using 0.5% 5-FU21,22 and 5.9% (1/17) of patients using 5% 5-FU.17 Only four studies provided any information about the proportion of patients completing the designated treatment period. Table 3 presents the available information on the number of patients ceasing treatment, patient preference for treatments, and withdrawals as a result of adverse events.
|Early cessation of treatment||Patient preference||Number of patients withdrawing because of adverse events|
|Bercovitch18||Treatment period between 2 and 4 weeks. Mean duration of treatment, 15.8 days||Not measured or reported||5% (1/20) – severe reaction to treatment|
|Hantash et al.11||No information provided – unclear whether actual duration of treatment assessed||Not measured or reported||0|
|Jorizzo et al.20||11.0% (5/45) in 4-week 0.5% 5-FU treatment group||Not measured or reported||8.9% (24/207), but authors state no events caused by treatment|
|Jorizzo et al.12||Treatment period 1 week. No information provided – unclear whether actual duration of treatment assessed||Not measured or reported||0|
|Jury et al.19||No information provided – unclear whether actual duration of treatment assessed||Not measured or reported||Not reported|
|Krawtchenko et al.14||3.8% (1/26) refused second treatment cycle of imiquimod||Patient preference not measured or reported||Not reported|
|Kurwa et al.17||No information provided – unclear whether actual duration of treatment assessed||Not measured or reported||18.0% (3/17), one event because of contact sensitivity to 5% 5-FU|
|Loven et al.5||Four patients prematurely discontinued treatment because of irritation with 0.5% 5-FU, eight with 5% 5-FU, and four with both treatments (total of 16/20 patients discontinued treatment early)||85.0% (17/20) preferred 0.5% 5-FU; 15.0% (3/20) preferred 5% 5-FU||5.0% (1/21) – not treatment related|
|Ostertag et al.16||No information provided – unclear whether actual duration of treatment assessed||Not measured or reported||0|
|Smith et al.22||17.0% (2/12) in 0.5% 5-FU treatment group||Not measured or reported||3.0% (1/36) because of severe reaction to 0.5% 5-FU|
|Smith et al.15||No information provided – unclear whether actual duration of treatment assessed||79% and 68% patients very or completely satisfied with DFS and 5% 5-FU, respectively||3.0% (1/29) – not treatment related|
|Tanghetti and Werschler13||Treatment period was 2–4 weeks – no information provided about duration of actual treatment||Not measured or reported||0|
|Weiss et al.21||2.4% (1/38) and 5.0% (2/41) from the 2- and 4-week treatment groups, respectively||Not measured or reported||4.0% (7/177) – three as a result of treatment effects|
Methodologic quality of the included studies
The majority of studies were poorly reported (Table 4), with only five studies providing any detail about randomization methods5,12,14,16,19 and only two of these adequately describing allocation concealment.12,16 Only one study was double blind,12 and four were single blind (outcome assessment only).5,13,15,19 Although most studies claimed to undertake intention-to-treat analysis, only five included all randomized patients in the analysis.14–16,21,22 Insufficient baseline data were provided in two studies,20,22 preventing the comparison of treatment groups. Eight studies did not report fully on their pre-specified outcomes; commonly, studies reported percentages without giving either the denominator or numerator, or did not provide standard deviations or ranges for the data when reporting means or medians.5,13,15,16,19–22 In summary, most of the included studies were at moderate to high risk of bias, and therefore the results should be interpreted with caution and few, if any, generalizations could be made.
|Random sequence generation||Allocation concealment||Blinding during study||Outcome assessment||Intention-to-treat analysis||Nonselective reporting||Validity of outcome assessment|
|Bercovitch18||Unclear||Unclear||Unclear, but probably||Unclear||No||Yes||Lesions were counted in triplicate prior to study, no information about count after study|
|Hantash et al.11||Unclear||Unclear||No||Unclear||Yes||Yes||Number and location of lesions were charted on a diagram of the head at enrollment and compared at follow-up|
|Jorizzo et al.20||Unclear||Unclear||Unclear||Unclear||No||No||No information provided about lesion count|
|Jorizzo et al.12||Yes||Yes||Yes||Yes||No||Yes||Visible and palpable lesions counted by same evaluator at each review|
|Jury et al.19||Yes||Unclear||No||Yes||No||No||Lesion count and lesion map at each review, and clinical photographs taken|
|Krawtchenko et al.14||Yes||Unclear||Unclear||Unclear||Unclear||No||Lesions documented on body grid charts with raster and photographs|
|Kurwa et al.17||Unclear||Unclear||No||Unclear||No||Yes||Clinical margins of AKs on treated areas traced, digitalized, and mean lesion areas calculated|
|Loven et al.5||Yes||Unclear||No||Yes||No||No||Visible and palpable lesions counted|
|Ostertag et al.16||Yes||Yes||No||Unclear||Yes||No||Visible lesions counted|
|Smith et al.22||Unclear||Unclear||Unclear||Unclear||No||No||Clinical photographs of each lesion and full face taken at baseline|
|Smith et al.15||Unclear||Unclear||No||Yes||No||No||Lesions selected, marked, mapped, and photographed|
|Tanghetti and Werschler13||Unclear||Unclear||No||Yes||No||No||No information provided about lesion count|
|Weiss et al.21||Unclear||Unclear||Unclear||Unclear||Yes||Yes||Lesions counted|
Our systematic review provides valuable evidence to indicate that about one-half of patients using 5-FU for the treatment of AK lesions can expect complete clearance; that, overall, an 80% reduction in lesion count can be expected; and that a 90% reduction in total lesion count is likely. Most patients (about two-thirds) can expect to require retreatment after 1 year, and although few patients stop treatment as a result of adverse events, up to one-half may not be able to complete the full treatment course. The quality of the studies providing this evidence is, however, poor. Evidence on alternative treatments (studied head to head with 5-FU) is limited.
Most studies were small, and only two12,16 reported sample size calculations to ensure adequate power. The three studies comparing 0.5% 5-FU with placebo12,20,21 involved 528 participants and were adequately powered, based on the rationale provided in one of the studies.12 Of the remaining studies (excluding that which reported a sample size calculation), the number of participants ranged from 17 for the split hand study comparing 5% 5-FU with ALA PDT17 to 75 for the parallel group study comparing 5% 5-FU, cryotherapy, and imiquimod,14 although the latter study appears to have been adequately powered based on the reported outcomes. Two studies contained three parallel groups and involved a total of 23 and 36 patients, respectively, and were clearly underpowered.11,22 The small number of participants in most studies limits generalizations being drawn from the results. This is disappointing as high-quality evidence on comparative treatments is highly desirable. The conflicting results from the two studies comparing 5% 5-FU with imiquimod highlight the need to have adequately powered studies, robust outcome measures, and study designs that are, as far as possible, at low risk of bias.
Incomplete or no reporting of randomization,11,13,15,17,18,20–22 allocation concealment,5,11,13,15,17–22 blinding,5,11,13,15–22 raw data,5,13,20–22 and CIs or standard deviations5,16,19–21 led to a considerable loss of information, which limited data synthesis across studies. Had this information been available, meta-analysis might have been possible, leading to much more precise estimations of effect. The duration of follow-up in seven studies was less than 8 weeks – the recommended length of time for the maximum effectiveness of treatment to become apparent. It is possible that a further reduction in the number of lesions after the cessation of follow-up would have occurred. This is of concern in studies comparing 5-FU with a more rapidly acting treatment, such as PDT, and would bias the results against 5-FU.
The lack of consistency in outcome measures further limited the opportunities for data synthesis. Also of note was the limited focus on patient-centered outcomes, with few studies systematically or comprehensively measuring patient satisfaction with either the treatment itself or its outcome. This is surprising, given that local site reactions are a natural consequence of treatment, and that the effectiveness of treatment is directly related to the seriousness of this reaction and the duration of treatment. Although few patients actually withdrew from any of the studies as a result of the adverse events associated with 5-FU, four studies reported early cessation of treatment by 4%,21 11%,20 17%,22 and a very high 86% of patients in the study comparing 5% 5-FU with 0.5% 5-FU.5 Several of the other studies did not specify the intended length of the treatment period, but rather stated that patients applied 5-FU for between 2 and 4 weeks, or between 2 and 7 weeks. Nor did these studies provide any detail about the actual length of time that the trial participants used the treatment. The studies by Jorizzo et al.20 and Weiss et al.21 clearly showed that the efficacy of 0.5% 5-FU was linked to the treatment duration, but studies of this nature have not been conducted with 5% 5-FU. Nevertheless, the length of time that patients can tolerate treatment is an important clinical issue, and the lack of information provided in these studies hinders informed decision making by both the clinician and patient.
A further methodologic concern was the lack of objective methods of assessment of the number of AK lesions. Most studies simply counted the lesions at baseline and follow-up, and compared the counts. Four studies produced a physical map of the lesions (either by photography or by charting the location of lesions onto a diagram),11,15,19,22 whereas other studies simply counted the lesions at each assessment. A longitudinal study of the natural history of AK found a very high turnover of AK, with large numbers developing, regressing, and recurring over time.24 Because of the labile nature of these lesions, studies investigating treatment options for their eradication need to ensure that they are able to accurately trace the evolution of all lesions included at baseline. None of the included studies could make this claim.
We conducted a systematic and comprehensive search but were unable to locate any RCTs comparing 5% 5-FU with placebo, no studies determining an optimal duration of treatment, and only two studies comparing 5-FU with imiquimod (another commonly used topical treatment). The conflicting results from these two studies highlight the need to have adequately powered studies, robust outcome measures, and study designs that are, as far as possible, at low risk of bias. Clearly, 5% 5-FU is considered to be clinically effective – Valeant Pharmaceuticals have reported that more than 30 million prescriptions have been written for Efudex® worldwide over the last 30 years.25 This figure becomes even more startling when it is considered that it is not the treatment of choice in continental Europe for the removal of AK lesions, unlike areas such as Australia, South Africa, and southern USA, where there is a high prevalence of these lesions. Presumably, clinicians in these countries have adopted this treatment, have found it to be clinically effective and efficient, and have had insufficient complaints from patients to consider alternative treatments – an example of “eminence-based treatment” rather than “evidence-based treatment.”26
Nevertheless, there are consequences of the lack of quality RCTs investigating the treatment of AK with 5% 5-FU. There is a lack of good quality empirical evidence to inform clinicians about which of their patients will gain the greatest benefit from this treatment, or the characteristics of AK lesions that are most, or least, likely to be cured. There is also insufficient evidence to enable clinicians to make informed choices between 5-FU and imiquimod, and between 5-FU and other treatment modalities, such as facial resurfacing or PDT. There is insufficient evidence on patient satisfaction to enable consumers to make informed treatment choices. Also, there is virtually no evidence about the long-term effectiveness of this treatment. These gaps clearly need to be addressed, given the high and increasing worldwide prevalence of AKs over recent decades, particularly in regions with high exposure to UV light.1
Topical 5-FU therapy:
- 1is not an extremely effective therapy;
- 2typically only affects dysplastic areas of skin;
- 3appears to be relatively well tolerated in practice;
- 4typically produces an excellent cosmetic reaction when used on the face;
- 5may be associated with a photosensitive reaction;
- 6works best on the legs;
- 7prevents new AKs from forming in treated areas;
- 8needs to be continued for 4 weeks to obtain the full effect;
- 9is also listed on the PBS in Australia for use on Bowen's disease (intraepidermal SCCs);
- 10has been utilized in two different strengths.
Answers found on next page
- 9HigginsJPT, GreenS (eds) Cochrane Handbook for Systematic Reviews of Interventions 5.0.0 [updated, February 2008]. The Cochrane Collaboration, 2008. Available from http://www.cochrane-handbook.org[accessed on 27 March 2008].
- 10The Nordic Cochrane Centre. Review Manager (Revman) [Computer Program], Version 4.2 for Windows. Copenhagen: The Nordic Cochrane Centre, 2003.
- 13Comparison of 5% 5-fluorouracil cream and 5% imiquimod cream in the management of actinic keratoses on the face and scalp. J Drugs Dermatol 2007; 6: 144–147.,
- 14A 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. Br J Dermatol 2007; 157(Suppl. 2): 34–40., , , et al .
- 15Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drugs Dermatol 2006; 5: 156–159., , .
- 22Short incubation PDT versus 5-FU in treating actinic keratoses. J Drugs Dermatol 2003; 2: 629–635., , , et al .
- 23Valeant Pharmaceutical North America. EFUDEX® (Fluorouracil) Topical Solutions and Cream: Product Information. Costa Mesa, CA: Valeant Pharmaceutical North America, 2005.
- 25Valeant Pharmaceuticals. EFUDEX® (Fluorouracil) Website. URL http://www.efudex.com/[accessed on 15 December 2007].