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Review
, 12 (12), CD004415

Interventions for Actinic Keratoses

Affiliations
Review

Interventions for Actinic Keratoses

Aditya K Gupta et al. Cochrane Database Syst Rev.

Abstract

Background: Actinic keratoses are a skin disease caused by long-term sun exposure, and their lesions have the potential to develop into squamous cell carcinoma. Treatments for actinic keratoses are sought for cosmetic reasons, for the relief of associated symptoms, or for the prevention of skin cancer development. Detectable lesions are often associated with alteration of the surrounding skin (field) where subclinical lesions might be present. The interventions available for the treatment of actinic keratoses include individual lesion-based (e.g. cryotherapy) or field-directed (e.g. topical) treatments. These might vary in terms of efficacy, safety, and cosmetic outcomes.

Objectives: To assess the effects of topical, oral, mechanical, and chemical interventions for actinic keratosis.

Search methods: We searched the following databases up to March 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), and LILACS (from 1982). We also searched trials registers, conference proceedings, and grey literature sources.

Selection criteria: Randomised controlled trials (RCTs) comparing the treatment of actinic keratoses with either placebo, vehicle, or another active therapy.

Data collection and analysis: At least two authors independently abstracted data, which included adverse events, and assessed the quality of evidence. We performed meta-analysis to calculate a weighted treatment effect across trials, and we expressed the results as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes (e.g. participant complete clearance rates), and mean difference (MD) and 95% CI for continuous outcomes (e.g. mean reduction in lesion counts).

Main results: We included 83 RCTs in this review, with a total of 10,036 participants. The RCTs covered 18 topical treatments, 1 oral treatment, 2 mechanical interventions, and 3 chemical interventions, including photodynamic therapy (PDT). Most of the studies lacked descriptions of some methodological details, such as the generation of the randomisation sequence or allocation concealment, and half of the studies had a high risk of reporting bias. Study comparison was difficult because of the multiple parameters used to report efficacy and safety outcomes, as well as statistical limitations. We found no data on the possible reduction of squamous cell carcinoma.The primary outcome 'participant complete clearance' significantly favoured four field-directed treatments compared to vehicle or placebo: 3% diclofenac in 2.5% hyaluronic acid (RR 2.46, 95% CI 1.66 to 3.66; 3 studies with 420 participants), 0.5% 5-fluorouracil (RR 8.86, 95% CI: 3.67 to 21.44; 3 studies with 522 participants), 5% imiquimod (RR 7.70, 95% CI 4.63 to 12.79; 9 studies with1871 participants), and 0.025% to 0.05% ingenol mebutate (RR 4.50, 95% CI 2.61 to 7.74; 2 studies with 456 participants).It also significantly favoured the treatment of individual lesions with photodynamic therapy (PDT) compared to placebo-PDT with the following photosensitisers: aminolevulinic acid (ALA) (blue light: RR 6.22, 95% CI 2.88 to 13.43; 1 study with 243 participants, aminolevulinic acid (ALA) (red light: RR 5.94, 95% CI 3.35 to 10.54; 3 studies with 422 participants), and methyl aminolevulinate (MAL) (red light: RR 4.46, 95% CI 3.17 to 6.28; 5 studies with 482 participants). ALA-PDT was also significantly favoured compared to cryotherapy (RR 1.31, 95% CI 1.05 to 1.64).The corresponding comparative risks in terms of number of participants completely cleared per 1000 were as follows: 313 with 3% diclofenac compared to 127 with 2.5% hyaluronic acid; 136 with 0.5% 5-fluorouracil compared to 15 with placebo; 371 with 5% imiquimod compared to 48 with placebo; 331 with ingenol mebutate compared to 73 with vehicle; 527 to 656 with ALA/MAL-PDT treatment compared to 89 to 147 for placebo-PDT; and 580 with ALA-PDT compared to 443 with cryotherapy.5% 5-fluorouracil efficacy was not compared to placebo, but it was comparable to 5% imiquimod (RR 1.85, 95% Cl 0.41 to 8.33).A significant number of participants withdrew because of adverse events with 144 participants affected out of 1000 taking 3% diclofenac in 2.5% hyaluronic acid, compared to 40 participants affected out of 1000 taking 2.5% hyaluronic acid alone, and 56 participants affected out of 1000 taking 5% imiquimod compared to 21 participants affected out of 1000 taking placebo.Based on investigator and participant evaluation, imiquimod treatment and photodynamic therapy resulted in better cosmetic outcomes than cryotherapy and 5-fluorouracil.

Authors' conclusions: For individual lesions, photodynamic therapy appears more effective and has a better cosmetic outcome than cryotherapy. For field-directed treatments, diclofenac, 5-fluorouracil, imiquimod, and ingenol mebutate had similar efficacy, but their associated adverse events and cosmetic outcomes are different. More direct comparisons between these treatments are needed to determine the best therapeutic approach.

Conflict of interest statement

Dr Aditya Gupta, lead author of this review, participated in a clinical trial sponsored by DUSA in 2004, which was excluded from the review because it did not meet the inclusion criteria.

Dr Stephen Keohane, clinical referee for this review, states: "I have been paid for lectures and advisory boards by Galderma, Almirall, Intendis, Inc., Shire, and Bayer."

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Funnel plot of comparison: 15 Imiquimod versus placebo: different concentrations, outcome: 15.1 Participant complete clearance.
4
4
Funnel plot of comparison: 50 MAL‐PDT (red light) versus placebo‐PDT (red light), outcome: 50.1 Participant complete clearance.
1.1
1.1
Comparison 1 Adapalene gel versus placebo, Outcome 1 Global Improvement Indices (investigator)‐cleared.
1.2
1.2
Comparison 1 Adapalene gel versus placebo, Outcome 2 Mean changes in lesion counts.
1.3
1.3
Comparison 1 Adapalene gel versus placebo, Outcome 3 Withdrawal due to adverse events.
1.4
1.4
Comparison 1 Adapalene gel versus placebo, Outcome 4 Minor adverse events excluding skin irritation: dermatitis.
2.1
2.1
Comparison 2 0.1% adapalene vs 0.3% adapalene, Outcome 1 Global Improvement Indices (investigator)‐cleared.
2.2
2.2
Comparison 2 0.1% adapalene vs 0.3% adapalene, Outcome 2 Mean changes in lesion counts.
2.3
2.3
Comparison 2 0.1% adapalene vs 0.3% adapalene, Outcome 3 Withdrawal due to adverse events.
2.4
2.4
Comparison 2 0.1% adapalene vs 0.3% adapalene, Outcome 4 Minor adverse events excluding skin irritation: dermatitis.
3.1
3.1
Comparison 3 Arotinoid Methyl Sulfone (Ro 14‐9706) versus Tretinoin, Outcome 1 Mean percentage of reduction in lesion counts.
4.1
4.1
Comparison 4 Calcipotriol (vitamin D) versus placebo, Outcome 1 Mean changes in lesion counts.
4.2
4.2
Comparison 4 Calcipotriol (vitamin D) versus placebo, Outcome 2 Cosmetic outcomes: Reduction in total cosmetic appearance score.
5.1
5.1
Comparison 5 1% colchicine cream versus 0.5% colchicine cream, Outcome 1 Participant complete clearance.
5.2
5.2
Comparison 5 1% colchicine cream versus 0.5% colchicine cream, Outcome 2 Mean reduction in lesion counts‐total.
5.3
5.3
Comparison 5 1% colchicine cream versus 0.5% colchicine cream, Outcome 3 Mean reduction in lesion counts‐per anatomical locations.
5.4
5.4
Comparison 5 1% colchicine cream versus 0.5% colchicine cream, Outcome 4 Cosmetic outcomes: Number of participants with decreased infiltration and disappearance of crust.
6.1
6.1
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 1 Investigator Global Improvement Indices‐completely improved.
6.2
6.2
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 2 Participant Global Improvement Indices‐completely improved.
6.3
6.3
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 3 Participant complete clearance at end of treatment (>56 days).
6.4
6.4
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 4 Participant complete clearance (target lesions).
6.5
6.5
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 5 Participant complete clearance (all lesions).
6.6
6.6
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 6 Participant complete clearance for 30 day treatment by locations.
6.7
6.7
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 7 Participant complete clearance for 60 day treatment by locations.
6.8
6.8
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 8 Participant complete clearance for 90 day treatment by locations.
6.9
6.9
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 9 Participant complete clearance in immunosuppressed participants.
6.10
6.10
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 10 Participant partial (>75%) clearance in immunosuppressed participants.
6.11
6.11
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 11 Mean reduction of lesion counts (30‐90 days ): At the end of study.
6.12
6.12
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 12 Mean reduction of lesion counts (30‐90 days): 30 day follow‐up.
6.13
6.13
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 13 Withdrawal due to adverse events.
6.14
6.14
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 14 Minor adverse event: body as a whole : in general.
6.15
6.15
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 15 Minor adverse event: body as a whole : "flu".
6.16
6.16
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 16 Minor adverse event:: body as a whole : infection.
6.17
6.17
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 17 Minor adverse event: cardiovascular: in general.
6.18
6.18
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 18 Minor adverse event: cardiovascular: sinus bradycardia.
6.19
6.19
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 19 Minor adverse event: dermatological: bursitis.
6.20
6.20
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 20 Minor adverse event: dermatological: dry skin.
6.21
6.21
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 21 Minor adverse event: dermatological: herpes zoster.
6.22
6.22
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 22 Minor adverse event: dermatological: rash vesiculobullous.
6.23
6.23
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 23 Minor adverse event::dermatological: seborrhoea.
6.24
6.24
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 24 Minor adverse event: dermatological: skin exfoliation.
6.25
6.25
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 25 Minor adverse event: dermatological: ulcerated skin.
6.26
6.26
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 26 Minor adverse event: digestive : in general.
6.27
6.27
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 27 Minor adverse event: hemic and lymphatic: in general.
6.28
6.28
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 28 Minor adverse event: metabolic and nutritional disorders : in general.
6.29
6.29
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 29 Minor adverse event: musculoskeletal and connective tissue: in general.
6.30
6.30
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 30 Minor adverse event: musculoskeletal and connective tissue: hypokinesia.
6.31
6.31
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 31 Minor adverse event: nervous system: in general.
6.32
6.32
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 32 Minor adverse event: nervous system: headache.
6.33
6.33
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 33 Minor adverse event: nervous system: hyperaesthesia.
6.34
6.34
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 34 Minor adverse event: nervous system: paraesthesia.
6.35
6.35
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 35 Minor adverse event: respiratory: in general.
6.36
6.36
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 36 Minor adverse event: respiratory: bronchitis.
6.37
6.37
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 37 Minor adverse event: respiratory: pharyngitis.
6.38
6.38
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 38 Minor adverse event: respiratory: upper respiratory tract infection.
6.39
6.39
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 39 Minor adverse event: special senses: in general.
6.40
6.40
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 40 Minor adverse event: urogenital: in general.
7.1
7.1
Comparison 7 3% diclofenac in 2.5% hyaluronic acid versus 5% imiquimod, Outcome 1 Investigator Global Improvement Indices‐Complete improvement.
7.2
7.2
Comparison 7 3% diclofenac in 2.5% hyaluronic acid versus 5% imiquimod, Outcome 2 Participant Global Improvement Indices‐Complete improvement.
8.1
8.1
Comparison 8 2‐(Difluoromethyl)‐dl‐ornithine (DFMO) versus placebo, Outcome 1 Mean reduction in lesions counts.
9.1
9.1
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 1 Participant complete clearance.
9.2
9.2
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 2 Mean reduction in lesion counts.
9.3
9.3
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 3 Mean percentage of reduction in lesion counts.
9.4
9.4
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 4 Withdrawal due to adverse events.
9.5
9.5
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 5 Skin irritation.
9.6
9.6
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 6 Minor adverse event excluding skin irritation: body as a whole : in general.
9.7
9.7
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 7 Minor adverse event excluding skin irritation: body as a whole : allergy.
9.8
9.8
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 8 Minor adverse event excluding skin irritation: body as a whole : "flu" or common cold.
9.9
9.9
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 9 Minor adverse event excluding skin irritation: musculoskeletal and connective tissue: in general.
9.10
9.10
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 10 Minor adverse event excluding skin irritation: musculoskeletal and connective tissue: soreness.
9.11
9.11
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 11 Minor adverse event excluding skin irritation:nervous system: headache.
9.12
9.12
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 12 Minor adverse event excluding skin irritation: respiratory: in general.
9.13
9.13
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 13 Minor adverse event excluding skin irritation: respiratory: sinusitis.
9.14
9.14
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 14 Minor adverse event excluding skin irritation: respiratory: upper respiratory tract infection.
9.15
9.15
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 15 Minor adverse event excluding skin irritation: special senses: in general.
9.16
9.16
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 16 Minor adverse event excluding skin irritation:special senses: eye irritation.
10.1
10.1
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 1 Participant complete clearance.
10.2
10.2
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 2 Withdrawal due to adverse events.
10.3
10.3
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 3 Skin irritation.
10.4
10.4
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 4 Minor adverse events excluding skin irritation: body as a whole : in general.
10.5
10.5
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 5 Minor adverse events excluding skin irritation: body as a whole : allergy.
10.6
10.6
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 6 Minor adverse events excluding skin irritation: body as a whole : "flu" or common cold.
10.7
10.7
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 7 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
10.8
10.8
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 8 Minor adverse events excluding skin irritation: nervous system: headache.
10.9
10.9
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 9 Minor adverse events excluding skin irritation: respiratory: in general.
10.10
10.10
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 10 Minor adverse events excluding skin irritation: respiratory: sinusitis.
10.11
10.11
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 11 Minor adverse events excluding skin irritation: special senses: in general.
10.12
10.12
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 12 Minor adverse events excluding skin irritation: special senses: eye irritation.
11.1
11.1
Comparison 11 0.5% 5‐FU versus ALA‐PDT, Outcome 1 Participant complete clearance.
11.2
11.2
Comparison 11 0.5% 5‐FU versus ALA‐PDT, Outcome 2 Withdrawal due to adverse events.
12.1
12.1
Comparison 12 5% 5‐FU with 0.05% tretinoin versus 5% 5‐FU with placebo, Outcome 1 Mean reduction in lesion counts.
13.1
13.1
Comparison 13 5% 5‐FU versus 5% imiquimod, Outcome 1 Participant complete clearance.
14.1
14.1
Comparison 14 5% 5‐FU versus cryotherapy, Outcome 1 Participant complete clearance.
15.1
15.1
Comparison 15 5% 5‐FU versus 10% masoprocol, Outcome 1 Investigator Global Improvement Indices ‐cleared.
15.2
15.2
Comparison 15 5% 5‐FU versus 10% masoprocol, Outcome 2 Mean reduction of lesion counts.
15.3
15.3
Comparison 15 5% 5‐FU versus 10% masoprocol, Outcome 3 Mean percentage of reduction of lesion counts.
15.4
15.4
Comparison 15 5% 5‐FU versus 10% masoprocol, Outcome 4 Withdrawal due to adverse events.
16.1
16.1
Comparison 16 5% 5‐FU versus carbon dioxide laser resurfacing, Outcome 1 Mean percentage of reduction of lesion counts.
16.2
16.2
Comparison 16 5% 5‐FU versus carbon dioxide laser resurfacing, Outcome 2 Withdrawal due to adverse events.
17.1
17.1
Comparison 17 5% 5‐FU versus Er:YAG laser resurfacing, Outcome 1 Withdrawal due to adverse events.
17.2
17.2
Comparison 17 5% 5‐FU versus Er:YAG laser resurfacing, Outcome 2 Skin irritation.
18.1
18.1
Comparison 18 5% 5‐FU versus Trichloroacetic acid peel, Outcome 1 Mean percentage of reduction in lesions.
19.1
19.1
Comparison 19 5% Imiquimod versus placebo, Outcome 1 Participant complete clearance‐number of doses.
19.2
19.2
Comparison 19 5% Imiquimod versus placebo, Outcome 2 Participant complete clearance in immunosuppressed participants.
19.3
19.3
Comparison 19 5% Imiquimod versus placebo, Outcome 3 Participant partial (>75%) clearance.
19.4
19.4
Comparison 19 5% Imiquimod versus placebo, Outcome 4 Participant partial (>75%) clearance in immunosuppressed participants.
19.5
19.5
Comparison 19 5% Imiquimod versus placebo, Outcome 5 Mean reduction in lesion counts.
19.6
19.6
Comparison 19 5% Imiquimod versus placebo, Outcome 6 Withdrawal due to adverse events.
19.7
19.7
Comparison 19 5% Imiquimod versus placebo, Outcome 7 Withdrawal due to adverse events in immunosuppressed participants.
19.8
19.8
Comparison 19 5% Imiquimod versus placebo, Outcome 8 Minor adverse events excluding skin irritation: body as a whole: in general.
19.9
19.9
Comparison 19 5% Imiquimod versus placebo, Outcome 9 Minor adverse events excluding skin irritation: body as a whole: "flu" or "cold".
19.10
19.10
Comparison 19 5% Imiquimod versus placebo, Outcome 10 Minor adverse events excluding skin irritation: digestive: in general.
19.11
19.11
Comparison 19 5% Imiquimod versus placebo, Outcome 11 Minor adverse events excluding skin irritation: digestive: nausea.
19.12
19.12
Comparison 19 5% Imiquimod versus placebo, Outcome 12 Minor adverse events excluding skin irritation: nervous system: in general.
19.13
19.13
Comparison 19 5% Imiquimod versus placebo, Outcome 13 Cosmetic outcome: decrease in roughness/dryness/scaliness of the skin.
20.1
20.1
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 1 Participant complete clearance.
20.2
20.2
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 2 Participant partial (>75%) clearance.
20.3
20.3
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 3 Mean percentage of reduction in lesion counts.
20.4
20.4
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: 'flu" or "cold".
20.5
20.5
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 5 Withdrawal due to adverse events.
20.6
20.6
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 6 Skin irritation.
20.7
20.7
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 7 Minor adverse events excluding skin irritation: body as a whole: pyrexia.
20.8
20.8
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 8 Minor adverse events excluding skin irritation: hemic and lymphatic: lymphadenopathy.
20.9
20.9
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 9 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
20.10
20.10
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 10 Minor adverse events excluding skin irritation: nervous system: fatigue.
20.11
20.11
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 11 Minor adverse events excluding skin irritation: nervous system: headache.
20.12
20.12
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 12 Minor adverse events excluding skin irritation: respiratory: cough.
20.13
20.13
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 13 Minor adverse events excluding skin irritation: respiratory: sinusitis.
20.14
20.14
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 14 Minor adverse events excluding skin irritation: respiratory: upper respiratory tract infection.
20.15
20.15
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 15 Minor adverse events excluding skin irritation: urogenital: urinary tract infection.
20.16
20.16
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 16 Cosmetic outcome: Participant's significantly or much improved cosmetic outcome assessed by investigator.
21.1
21.1
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 1 Participant complete clearance.
21.2
21.2
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 2 Participant partial (>75%) clearance.
21.3
21.3
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 3 Withdrawal due to adverse events.
21.4
21.4
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 4 Minor adverse events excluding skin irritation:body as a whole: in general.
21.5
21.5
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 5 Minor adverse events excluding skin irritation: body as a whole:"flu" or "cold".
21.6
21.6
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 6 Minor adverse events excluding skin irritation: digestive: in general.
21.7
21.7
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 7 Minor adverse events excluding skin irritation: digestive: nausea.
21.8
21.8
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 8 Minor adverse events excluding skin irritation: nervous system: in general.
21.9
21.9
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 9 Minor adverse events excluding skin irritation: nervous system: headache.
22.1
22.1
Comparison 22 5% imiquimod versus 5% 5‐FU, Outcome 1 Participant complete clearance.
22.2
22.2
Comparison 22 5% imiquimod versus 5% 5‐FU, Outcome 2 Cosmetic outcome: Investigator cosmetic outcome "excellent".
22.3
22.3
Comparison 22 5% imiquimod versus 5% 5‐FU, Outcome 3 Cosmetic outcome: normal skin surface.
23.1
23.1
Comparison 23 5% imiquimod versus cryotherapy, Outcome 1 Participant complete clearance.
24.1
24.1
Comparison 24 Ingenol mebutate (PEP005) versus placebo, Outcome 1 Participant complete clearance of target lesions.
24.2
24.2
Comparison 24 Ingenol mebutate (PEP005) versus placebo, Outcome 2 Participant complete clearance of all lesions.
24.3
24.3
Comparison 24 Ingenol mebutate (PEP005) versus placebo, Outcome 3 Participant partial (>75%) clearance of target lesions.
24.4
24.4
Comparison 24 Ingenol mebutate (PEP005) versus placebo, Outcome 4 Cosmetic outcomes: changes in pigmentation.
25.1
25.1
Comparison 25 Ingenol mebutate (PEP005) versus placebo: different concentrations, Outcome 1 Participant complete clearance of target lesions.
25.2
25.2
Comparison 25 Ingenol mebutate (PEP005) versus placebo: different concentrations, Outcome 2 Participant complete clearance of all lesions.
25.3
25.3
Comparison 25 Ingenol mebutate (PEP005) versus placebo: different concentrations, Outcome 3 Participant partial (>75%) clearance of target lesions.
25.4
25.4
Comparison 25 Ingenol mebutate (PEP005) versus placebo: different concentrations, Outcome 4 Cosmetic outcomes: changes in pigmentation.
26.1
26.1
Comparison 26 0.05% Ingenol mebutate (PEP005) versus placebo: number of doses, Outcome 1 Participant complete clearance of target lesions.
26.2
26.2
Comparison 26 0.05% Ingenol mebutate (PEP005) versus placebo: number of doses, Outcome 2 Participant complete clearance of all lesions.
26.3
26.3
Comparison 26 0.05% Ingenol mebutate (PEP005) versus placebo: number of doses, Outcome 3 Participant partial (>75%) clearance of target lesions.
27.1
27.1
Comparison 27 Isotretinoin versus vehicle, Outcome 1 Investigator global improvement indices‐completely cleared.
27.2
27.2
Comparison 27 Isotretinoin versus vehicle, Outcome 2 Mean reduction of lesion counts.
27.3
27.3
Comparison 27 Isotretinoin versus vehicle, Outcome 3 Withdrawal due to adverse events.
27.4
27.4
Comparison 27 Isotretinoin versus vehicle, Outcome 4 Skin irritation.
27.5
27.5
Comparison 27 Isotretinoin versus vehicle, Outcome 5 Severe‐Skin irritation.
28.1
28.1
Comparison 28 Masoprocol versus placebo, Outcome 1 Global improvement indices‐cured.
28.2
28.2
Comparison 28 Masoprocol versus placebo, Outcome 2 Mean reduction in lesion counts.
28.3
28.3
Comparison 28 Masoprocol versus placebo, Outcome 3 Withdrawal due to adverse events.
29.1
29.1
Comparison 29 1% nicotinamide versus placebo, Outcome 1 Mean percentage of reduction in lesion counts.
29.2
29.2
Comparison 29 1% nicotinamide versus placebo, Outcome 2 Withdrawal due to adverse events.
30.1
30.1
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 1 Participant complete clearance.
30.2
30.2
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 2 Participant partial (>75%) clearance.
30.3
30.3
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 3 Withdrawal due to adverse events.
30.4
30.4
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
30.5
30.5
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
30.6
30.6
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
30.7
30.7
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
30.8
30.8
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
30.9
30.9
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
30.10
30.10
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
30.11
30.11
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
30.12
30.12
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
30.13
30.13
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
31.1
31.1
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 1 Participant complete clearance.
31.2
31.2
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 2 Participant partial (>75%) clearance.
31.3
31.3
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 3 Withdrawal due to adverse events.
31.4
31.4
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
31.5
31.5
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
31.6
31.6
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
31.7
31.7
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
31.8
31.8
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
31.9
31.9
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
31.10
31.10
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
31.11
31.11
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
31.12
31.12
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
31.13
31.13
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
32.1
32.1
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 1 Participant complete clearance.
32.2
32.2
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 2 Participant partial (>75%) clearance.
32.3
32.3
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 3 Withdrawal due to adverse events.
32.4
32.4
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
32.5
32.5
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
32.6
32.6
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
32.7
32.7
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
32.8
32.8
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
32.9
32.9
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
32.10
32.10
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
32.11
32.11
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
32.12
32.12
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
32.13
32.13
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
33.1
33.1
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 1 Participant complete clearance.
33.2
33.2
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 2 Participant partial (>75%) clearance.
33.3
33.3
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 3 Withdrawal due to adverse events.
33.4
33.4
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
33.5
33.5
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
33.6
33.6
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
33.7
33.7
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
33.8
33.8
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
33.9
33.9
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
33.10
33.10
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
33.11
33.11
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
33.12
33.12
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
33.13
33.13
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
34.1
34.1
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 1 Participant complete clearance.
34.2
34.2
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 2 Participant partial (>75%) clearance.
34.3
34.3
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 3 Withdrawal due to adverse events.
34.4
34.4
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
34.5
34.5
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
34.6
34.6
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
34.7
34.7
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
34.8
34.8
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
34.9
34.9
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
34.10
34.10
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
34.11
34.11
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
34.12
34.12
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
34.13
34.13
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 13 Minor adverse events excluding skin irritation:skin and subcutaneous disorders: in general.
35.1
35.1
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 1 Participant complete clearance.
35.2
35.2
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 2 Participant partial (>75%) clearance.
35.3
35.3
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 3 Withdrawal due to adverse events.
35.4
35.4
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
35.5
35.5
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
35.6
35.6
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
35.7
35.7
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
35.8
35.8
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
35.9
35.9
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
35.10
35.10
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
35.11
35.11
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
35.12
35.12
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
35.13
35.13
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
36.1
36.1
Comparison 36 Sunscreen SPF 17 (8% 2‐ethyl‐hexyl p‐methoxycinnamate/2% 4‐tert‐butyl‐4‐methoxy‐4‐dibenzoylmethane) versus placebo, Outcome 1 Mean change in lesion counts.
37.1
37.1
Comparison 37 12.5% DL‐α‐tocopherol (vitamin E) versus placebo, Outcome 1 Mean reduction of lesion counts.
38.1
38.1
Comparison 38 Etretinate versus placebo, Outcome 1 Participant complete clearance.
39.1
39.1
Comparison 39 Carbon dioxide laser resurfacing versus 5% 5‐FU, Outcome 1 Mean percentage of reduction of lesion counts.
39.2
39.2
Comparison 39 Carbon dioxide laser resurfacing versus 5% 5‐FU, Outcome 2 Withdrawal due to adverse events.
40.1
40.1
Comparison 40 Carbon dioxide laser resurfacing versus Trichloroacetic acid peel, Outcome 1 Mean percentage of reduction of lesion counts.
40.2
40.2
Comparison 40 Carbon dioxide laser resurfacing versus Trichloroacetic acid peel, Outcome 2 Withdrawal due to adverse events.
41.3
41.3
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 3 Withdrawal due to adverse events.
41.4
41.4
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 4 Skin irritation.
41.5
41.5
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 5 Minor adverse events excluding skin irritation: dermatology: acne.
41.6
41.6
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 6 Minor adverse events excluding skin irritation: dermatology:crustea.
41.7
41.7
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 7 Minor adverse events excluding skin irritation: dermatology: infection.
41.8
41.8
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 8 Minor adverse events excluding skin irritation: dermatology: milia.
41.9
41.9
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 9 Minor adverse events excluding skin irritation: dermatology:pain.
41.10
41.10
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 10 Cosmetic outcomes: changes in pigmentation (hypo).
41.11
41.11
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 11 Cosmetic outcomes: scarring.
41.12
41.12
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 12 Cosmetic outcomes: improvement in photoageing score.
42.1
42.1
Comparison 42 Cryotherapy versus betulin‐based oleogel, Outcome 1 Participant complete clearance.
42.2
42.2
Comparison 42 Cryotherapy versus betulin‐based oleogel, Outcome 2 Participant partial (>75%) clearance.
43.1
43.1
Comparison 43 Cryotherapy versus 5% 5‐FU, Outcome 1 Participant complete clearance.
43.2
43.2
Comparison 43 Cryotherapy versus 5% 5‐FU, Outcome 2 Cosmetic outcomes: excellent global cosmetic outcome.
43.3
43.3
Comparison 43 Cryotherapy versus 5% 5‐FU, Outcome 3 Cosmetic outcomes: better skin appearance.
44.1
44.1
Comparison 44 Cryotherapy versus imiquimod, Outcome 1 Participant complete clearance.
44.2
44.2
Comparison 44 Cryotherapy versus imiquimod, Outcome 2 Cosmetic outcomes: excellent global cosmetic outcome.
44.3
44.3
Comparison 44 Cryotherapy versus imiquimod, Outcome 3 Cosmetic outcomes: better skin appearance.
45.2
45.2
Comparison 45 Cryotherapy versus MAL‐red light PDT, Outcome 2 Withdrawal due to adverse events.
45.3
45.3
Comparison 45 Cryotherapy versus MAL‐red light PDT, Outcome 3 Cosmetic outcomes: excellent or good cosmetic outcomes by investigator.
45.4
45.4
Comparison 45 Cryotherapy versus MAL‐red light PDT, Outcome 4 Cosmetic outcomes: excellent or good cosmetic outcomes by participant.
46.1
46.1
Comparison 46 Cryotherapy versus ALA‐red light PDT, Outcome 1 Participant complete clearance.
46.2
46.2
Comparison 46 Cryotherapy versus ALA‐red light PDT, Outcome 2 Skin irritation.
47.1
47.1
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 1 Participant complete clearance [1 treatment].
47.2
47.2
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 2 Participant complete clearance [1 or 2 treatments].
47.3
47.3
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 3 Participant complete clearance [1 or 2 treatments] by anatomical location.
47.4
47.4
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 4 Participant partial (> 75%) clearance [1 treatment].
47.5
47.5
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 5 Participant partial (>75%) clearance[1 or 2 treatments].
47.6
47.6
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 6 Participant partial (>75%) clearance [1 or 2 treatment] by anatomical location.
47.7
47.7
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 7 Skin irritation.
47.8
47.8
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 8 Minor adverse events excluding skin irritation: body as a whole: injury.
47.9
47.9
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 9 Minor adverse events excluding skin irritation: cardiovascular: hypertension.
47.10
47.10
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 10 Minor adverse events excluding skin irritation: dermatology: skin discolouration.
47.11
47.11
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 11 Minor adverse events excluding skin irritation: dermatology: skin hypertrophy.
47.12
47.12
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 12 Minor adverse events excluding skin irritation: nervous system: headache.
47.13
47.13
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 13 Cosmetic outcome: very good or good general cosmetic outcome.
48.1
48.1
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 1 Participant complete clearance.
48.2
48.2
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 2 Participant partial (>75%) clearance.
48.3
48.3
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 3 Cosmetic outcome: improvement in global response.
48.4
48.4
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 4 Cosmetic outcome: improvement in tactile roughness.
48.5
48.5
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 5 Cosmetic outcome: improvement in mottled hyperpigmentation.
49.1
49.1
Comparison 49 ALA‐red light PDT at different application times, Outcome 1 Participant complete clearance at 4 weeks.
49.2
49.2
Comparison 49 ALA‐red light PDT at different application times, Outcome 2 Participant complete clearance at 8 weeks.
49.3
49.3
Comparison 49 ALA‐red light PDT at different application times, Outcome 3 Minor adverse events excluding skin irritation: metabolic and nutritional disorders: elevated alanine transaminase (ALT).
49.4
49.4
Comparison 49 ALA‐red light PDT at different application times, Outcome 4 Minor adverse events excluding skin irritation: nervous system: headache.
49.5
49.5
Comparison 49 ALA‐red light PDT at different application times, Outcome 5 Minor adverse events excluding skin irritation: other: epistaxis (nose bleeding).
50.1
50.1
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 1 Participant complete clearance.
50.2
50.2
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 2 Participant partial (>75%) clearance.
50.3
50.3
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 3 Withdrawal due to adverse events.
50.4
50.4
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 4 Cosmetic outcome: improvement in global response.
50.5
50.5
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 5 Cosmetic outcome: improvement in tactile roughness.
50.6
50.6
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 6 Cosmetic outcome: improvement in mottled hyperpigmentation.
51.1
51.1
Comparison 51 ALA‐red light PDT vs cryotherapy, Outcome 1 Participant complete clearance.
51.2
51.2
Comparison 51 ALA‐red light PDT vs cryotherapy, Outcome 2 Skin irritation.
52.1
52.1
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 1 Participant complete clearance.
52.2
52.2
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 2 Participant partial (>75%) clearance.
52.3
52.3
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 3 Withdrawal due to adverse events.
52.4
52.4
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 4 Minor adverse event: nervous system: headache.
52.5
52.5
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 5 Cosmetic outcome: hyperpigmentation.
53.1
53.1
Comparison 53 MAL‐red light LED PDT versus MAL‐broad visible + water‐filtered infrared A PDT (1 or 2 treatments), Outcome 1 Participant complete clearance.
53.2
53.2
Comparison 53 MAL‐red light LED PDT versus MAL‐broad visible + water‐filtered infrared A PDT (1 or 2 treatments), Outcome 2 Participant partial (>75%) clearance.
54.1
54.1
Comparison 54 MAL‐red light LED PDT versus MAL‐daylight PDT, Outcome 1 Mean reduction in lesion counts.
55.1
55.1
Comparison 55 2h MAL‐day light PDT versus 3h MAL‐daylight PDT, Outcome 1 Mean reduction in lesion counts.
55.2
55.2
Comparison 55 2h MAL‐day light PDT versus 3h MAL‐daylight PDT, Outcome 2 Mean percentage of reduction in lesion counts.
56.1
56.1
Comparison 56 16% MAL‐daylight PDT versus 8% MAL‐daylight PDT, Outcome 1 Mean reduction in lesion counts.
57.1
57.1
Comparison 57 Single MAL‐red light PDT versus multiple MAL‐red light PDT (2 treatments 1 week apart), Outcome 1 Participant complete clearance.
57.2
57.2
Comparison 57 Single MAL‐red light PDT versus multiple MAL‐red light PDT (2 treatments 1 week apart), Outcome 2 Withdrawal due to adverse events.
58.1
58.1
Comparison 58 MAL‐ red light PDT vs cryotherapy, Outcome 1 Withdrawal due to adverse events.
59.1
59.1
Comparison 59 ALA‐red light PDT versus MAL‐red light PDT, Outcome 1 Mean reduction in lesion counts.
60.1
60.1
Comparison 60 Trichloroacetic acid peel versus 5% 5‐FU, Outcome 1 Mean percentage of reduction in lesions.
61.1
61.1
Comparison 61 Cryotherapy versus cryotherapy with betulin‐based oleogel, Outcome 1 Participant complete clearance.
61.2
61.2
Comparison 61 Cryotherapy versus cryotherapy with betulin‐based oleogel, Outcome 2 Participant partial (>75%) clearance.
62.1
62.1
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 1 Participant complete clearance at 6 months.
62.2
62.2
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 2 Mean reduction in lesion counts at 6 months.
62.3
62.3
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 3 Mean percentage of reduction in lesion counts at 6 months.
62.4
62.4
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 4 Minor adverse events excluding skin irritation: body as a whole: allergic reaction.
62.5
62.5
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 5 Minor adverse events excluding skin irritation: dermatology: hyperesthesia.
62.6
62.6
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 6 Minor adverse events excluding skin irritation: dermatology: skin discoloration.
62.7
62.7
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 7 Minor adverse events excluding skin irritation: dermatology: vesiculobullous rash.
62.8
62.8
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 8 Minor adverse events excluding skin irritation: digestive: cheilitis.
62.9
62.9
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 9 Minor adverse events excluding skin irritation: special senses: conjunctivitis.
62.10
62.10
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 10 Minor adverse events excluding skin irritation: special senses: eye irritation.
63.1
63.1
Comparison 63 (vehicle + cryotherapy) versus (0.5% 5‐FU + cryotherapy), Outcome 1 Participant complete clearance at 6 months.
63.2
63.2
Comparison 63 (vehicle + cryotherapy) versus (0.5% 5‐FU + cryotherapy), Outcome 2 Mean reduction in lesion counts at 6 months.
63.3
63.3
Comparison 63 (vehicle + cryotherapy) versus (0.5% 5‐FU + cryotherapy), Outcome 3 Mean percentage of reduction in lesion counts at 6 months.
64.1
64.1
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 1 Participant complete clearance of all lesions.
64.2
64.2
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 2 Participant complete clearance of target (cryotherapy treated) lesions.
64.3
64.3
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 3 Participant complete clearance of subclinical lesions.
64.4
64.4
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 4 Mean percentage of reduction in all lesion counts.
64.5
64.5
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 5 Mean percentage of reduction in target (cryotherapy treated) lesion counts.
64.6
64.6
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 6 Withdrawal due to adverse events.
64.7
64.7
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 7 Skin irritation.
64.8
64.8
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 8 Minor adverse events excluding skin irritation: body as a whole: fatigue.
64.9
64.9
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 9 Minor adverse events excluding skin irritation: digestive: nausea.
64.10
64.10
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 10 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
64.11
64.11
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 11 Minor adverse events excluding skin irritation: respiratory: upper respiratory tract infection.
64.12
64.12
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 12 Minor adverse events excluding skin irritation: respiratory: bronchitis.
64.13
64.13
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 13 Minor adverse events excluding skin irritation: respiratory: sinusitis.
64.14
64.14
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 14 Minor adverse events excluding skin irritation: special senses: conjunctivitis.
64.15
64.15
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 15 Cosmetic outcomes: Improved global photoageing score.
64.16
64.16
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 16 Cosmetic outcomes: Improved fine lines.
64.17
64.17
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 17 Cosmetic outcomes: Improved tactile roughness.
64.18
64.18
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 18 Cosmetic outcomes: Improved mottled pigmentation.
64.19
64.19
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 19 Cosmetic outcomes: Improved sallowness.
64.20
64.20
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 20 Cosmetic outcomes: cosmetic appearance score.
65.1
65.1
Comparison 65 Cryotherapy with imiquimod versus cryotherapy with vehicle, Outcome 1 Participant complete clearance of all lesions.
65.2
65.2
Comparison 65 Cryotherapy with imiquimod versus cryotherapy with vehicle, Outcome 2 Mean percentage of reduction in all lesion counts.
65.3
65.3
Comparison 65 Cryotherapy with imiquimod versus cryotherapy with vehicle, Outcome 3 Withdrawal due to adverse events.
65.4
65.4
Comparison 65 Cryotherapy with imiquimod versus cryotherapy with vehicle, Outcome 4 Skin irritation.

Update of

  • Cochrane Database Syst Rev. doi: 10.1002/14651858.CD004415

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