Intervenciones para la queratosis actínica
Resumen
Antecedentes
La queratosis actínica es una enfermedad de la piel causada por la exposición al sol a largo plazo, y las lesiones presentan el potencial de convertirse en carcinoma de células escamosas. Los tratamientos para la queratosis actínica son solicitados por razones estéticas, para el alivio de los síntomas asociados o para la prevención de la aparición de cáncer de piel. Las lesiones detectables a menudo se asocian con la alteración de la piel circundante (área) donde pueden estar presentes las lesiones subclínicas. Las intervenciones disponibles para el tratamiento de la queratosis actínica incluyen tratamientos basados en la lesión individual (p.ej. crioterapia) o dirigidos al área (p.ej. tópicos). Los mismos pueden variar en cuanto a la eficacia, la seguridad y los resultados estéticos.
Objetivos
Evaluar los efectos de las intervenciones tópicas, orales, mecánicas y químicas para la queratosis actínica.
Métodos de búsqueda
Se hicieron búsquedas en las siguientes bases de datos hasta marzo 2011: Registro Especializado del Grupo Cochrane de Piel (Cochrane Skin Group), CENTRAL en The Cochrane Library, MEDLINE (desde 2005), EMBASE (desde 2010) y LILACS (desde 1982). También se realizaron búsquedas en registros de ensayos, resúmenes de congresos y fuentes de literatura gris.
Criterios de selección
Ensayos controlados aleatorizados (ECA) que compararan el tratamiento de la queratosis actínica con placebo, un vehículo u otro tratamiento activo.
Obtención y análisis de los datos
Al menos dos revisores extrajeron los datos, que incluyeron eventos adversos, y evaluaron la calidad de la evidencia de forma independiente. Se realizó el metanálisis para calcular un efecto ponderado del tratamiento entre los ensayos, y los resultados se expresaron como cocientes de riesgos (CR) e intervalos de confianza (IC) del 95% para los resultados dicotómicos (p.ej. tasas de resolución completa de los participantes) y diferencia de medias (DM) e IC del 95% para los resultados continuos (p.ej. reducción media de los recuentos de la lesión).
Resultados principales
Se incluyeron 83 ECA en esta revisión, con un total de 10 036 participantes. Los ECA cubrieron 18 tratamientos tópicos, un tratamiento oral, dos intervenciones mecánicas y tres intervenciones químicas, incluido el tratamiento fotodinámico (TFD). La mayoría de los estudios carecieron de descripciones de algunos detalles metodológicos, como la generación de la secuencia de asignación al azar o la ocultación de la asignación, y la mitad de los estudios tuvieron un riesgo alto de sesgo de notificación. La comparación de los estudios fue difícil debido a los parámetros múltiples utilizados para informar los resultados de la eficacia y la seguridad, así como las limitaciones estadísticas. No se encontraron datos sobre la posible reducción del carcinoma de células escamosas.
El resultado primario de la “resolución completa del participante” favoreció significativamente a cuatro tratamientos dirigidos al área en comparación con el vehículo o el placebo: 3% de diclofenac en 2,5% de ácido hialurónico (CR 2,46; IC del 95%: 1,66 a 3,66; 3 estudios con 420 participantes), 0,5% 5‐fluorouracilo (CR 8,86; IC del 95%: 1,86 a 3,66: 3.67 a 21,44; 3 estudios con 522 participantes), 5% imiquimod (CR 7,70; IC del 95%: 4,63 a 12,79; 9 estudios con 1 871 participantes) y 0,025% a 0,05% mebutate de ingenol (CR 4,50; IC del 95%: 2,61 a 7,74; 2 estudios con 456 participantes).
También favoreció significativamente el tratamiento de lesiones individuales con terapia fotodinámica (TFD) en comparación con la TFD con placebo con los siguientes fotosensibilizantes: ácido aminolevulínico (ALA) (luz azul: CR 6,22; IC del 95%: 2,88 a 13,43; 1 estudio con 243 participantes, ácido aminolevulínico (ALA) (luz roja: CR 5,94; IC del 95%: 3,35 a 10,54; 3 estudios con 422 participantes) y metil aminolevulinato (MAL) (luz roja: CR 4,46; IC del 95%: 3,17 a 6,28; 5 estudios con 482 participantes). El AAL‐TFD también fue superior significativamente en comparación con la crioterapia (CR 1,31; IC del 95%: 1,05 a 1,64).
Los riesgos comparativos correspondientes en cuanto al número de participantes con resolución completa por 1000 fueron los siguientes: 313 con diclofenac al 3% en comparación con 127 con ácido hialurónico al 2,5%; 136 con 5‐fluorouracilo al 0,5% en comparación con 15 con placebo; 371 con imiquimod al 5% en comparación con 48 con placebo; 331 con mebutate de ingenol en comparación con 73 con vehículo; 527 a 656 con tratamiento con ALA/MAL‐PDT en comparación con 89 a 147 con tratamiento con placebo‐PDT y 580 con ALA‐PDT en comparación con 443 con crioterapia.
La eficacia del 5‐fluorouracilo al 5% no se comparó con el placebo, aunque fue equivalente al imiquimod al 5% (CR 1,85; IC del 95%: 0,41 a 8,33).
Un número significativo de participantes se retiró debido a los eventos adversos con 144 de 1000 participantes afectados de los que recibieron diclofenac al 3% en ácido hialurónico al 2,5%, en comparación con 40 de 1000 participantes afectados de los que recibieron ácido hialurónico al 2,5% solo y 56 de 1000 participantes afectados de los recibieron imiquimod al 5% en comparación con 21 de 1000 participantes afectados de los que recibieron placebo.
Sobre la base de la evaluación de los investigadores y los participantes, el tratamiento con imiquimod y la terapia fotodinámica produjeron mejores resultados estéticos que la crioterapia y el 5‐fluorouracilo.
Conclusiones de los autores
Para las lesiones individuales, el tratamiento fotodinámico parece más efectivo y presenta un resultado estético mejor que la crioterapia. Para los tratamientos dirigidos al área, el diclofenac, el 5‐fluorouracilo, el imiquimod y el mebutato de ingenol tuvieron una eficacia similar, aunque los eventos adversos asociados y los resultados estéticos son diferentes. Se necesitan comparaciones más directas entre estos tratamientos para determinar el mejor enfoque terapéutico.
PICOs
Resumen en términos sencillos
Intervenciones para la queratosis actínica
La queratosis actínica es una enfermedad de la piel causada por la exposición al sol a largo plazo. La piel lesionada muestra manchas pequeñas, rojas, ásperas, escamosas y planas, denominadas queratosis actínica o lesiones, que se sienten como parches de piel seca. Los síntomas como la hemorragia y el dolor pueden asociarse con la queratosis actínica. Además, la queratosis actínica tiene el potencial de convertirse en cáncer de piel si no se trata. Las razones del tratamiento pueden incluir la apariencia estética, el alivio de los síntomas o la prevención del cáncer de piel. El tratamiento puede dirigirse a las lesiones individuales o a las áreas más grandes de la piel donde ocurren varias lesiones visibles y menos visibles (tratamiento dirigido al área).
Esta revisión sistemática incluyó resultados de 83 ensayos clínicos controlados aleatorizados que evaluaron 24 tratamientos, con un total de 10 036 participantes diagnosticados con queratosis actínica. Se incluyeron 18 cremas o geles tópicos aplicados en un área de la piel por los participantes: adapalene gel, aretinoide metilsulfona (Ro 14‐9706), oleogel a base de betulina, calcipotriol (vitamina D), colchicina, diclofenaco, 2‐(difluorometil)‐dl‐ornitina (DFMO), 5‐fluorouracilo, ß‐1,3‐D‐glucano, imiquimod, mebutate de ingenol (PEP005), isotretinoína, masoprocol, nicotinamida, resiquimod, protector solar, DL‐α‐tocoferol (vitamina E) y tretinoína. Un tratamiento, el etretinato, se administró por vía oral. El personal clínico administró dos tratamientos mecánicos (dióxido de carbono y rejuvenecimiento con láser Er:YAG) en un área de la piel, y administraron tres tratamientos químicos: crioterapia en lesiones individuales, terapia fotodinámica en lesiones individuales o en un área de la piel, y exfoliación con ácido tricloroacético en un área de la piel.
Los efectos clínicos resultantes del tratamiento de la queratosis actínica se informaron de un modo diferente entre los estudios. A pesar de esta inconsistencia, puede establecerse la conclusión de existen varias opciones efectivas de tratamiento para la queratosis actínica. La queratosis actínica fue tratada de forma exitosa con crioterapia, diclofenac, 5‐fluorouracilo, imiquimod, mebutato de ingenol, tratamiento fotodinámico, restauración y exfoliación con ácido tricloroacético. Estos diferentes tratamientos generalmente fueron equivalentes en cuanto a su efectividad. La irritación de la piel se asoció con algunos de estos tratamientos, como el diclofenac y el 5‐fluorouracilo, aunque otros efectos secundarios fueron poco comunes. La apariencia estética final varía de un tratamiento a otro. El tratamiento con imiquimod y el tratamiento fotodinámico dieron lugar a una mejor apariencia estética que el tratamiento con crioterapia y 5‐fluorouracilo.
El tratamiento fotodinámico proporciona mejores resultados terapéuticos y estéticos que la crioterapia para las lesiones individuales. Para los tratamientos dirigidos al área, el diclofenac, el 5‐fluorouracilo, el imiquimod y el mebutato de ingenol son buenas opciones asociadas con diferentes efectos secundarios y resultados estéticos. Por lo tanto, la elección de la opción de tratamiento para la queratosis actínica depende del número de lesiones, los resultados deseados por el individuo y la tolerancia a los tratamientos.
Authors' conclusions
Background
Description of the condition
Disease definition
Actinic keratoses are scaly lesions on the skin resulting from abnormal growth of atypical epidermal keratinocytes. They are localised at the surface of the skin on the sun‐exposed parts of the face or hands, particularly among older fair‐skinned individuals. Actinic keratoses are markers for increased rate of non‐melanoma skin cancer (Ramsay 2003) and shows the morphological and histological features of squamous cell carcinoma (Cockerell 2000; Feldman 2011). An actinic keratosis could be considered a precancerous lesion or carcinoma in situ based on the fact that the majority of invasive squamous cell carcinomas arise from actinic keratoses. Actinic keratoses are confined to the epidermis, whereas squamous cell carcinoma extends more deeply into the dermis. Thus, to limit the morbidity and mortality associated with squamous cell carcinoma, treatment of actinic keratoses is strongly recommended.
Actinic keratosis is also known as solar keratosis, senile keratosis, senile hyperkeratosis, keratoma senile, keratosis senilis, and actinic cheilitis (actinic keratosis on the lip) (Marks 1993; Rigel 2008; Schwartz 1997).
Clinical Features
The conventional clinical actinic keratosis lesion is a pink, red, or brown scaly patch on the skin, less than one centimetre in diameter (Roewert‐Huber 2007). Often, the scaliness of a lesion can be felt before it can be seen; this may progress into thickened or hypertrophic (increased bulk, due to an increase in lesion size) lesions. Actinic keratoses can be clinically graded with grade 1, slightly palpable; grade 2, moderately thick and visible; and grade 3, very thick and hyperkeratotic (Cockerell 2000; Olsen 1991). Accurate clinical diagnosis requires careful observation under adequate lighting conditions and palpation of the lesion texture (Marks 1993). Actinic keratoses are diagnosed histologically with a skin biopsy (Cockerell 2000; Marks 1993). Detectable actinic keratosis lesions are often associated with field change where the surrounding skin is also altered, and subclinical lesions may be present (Vatve 2007).
There are different classifications based on the clinical appearance of actinic keratoses: atrophic, hyperkeratotic, bowenoid, acantholytic, lichenoid, and pigmented (Rigel 2008; Roewert‐Huber 2007). Atrophic actinic keratoses are dry, scaly‐appearing lesions on a reddened base (due to dilated blood capillaries) without distinct margins. Hyperkeratotic actinic keratoses are papules and plaques with scale or scale‐crust that also possibly have cutaneous horns or conical masses. Bowenoid actinic keratoses are scaling red plaques with sharply‐established borders that simulate Bowen's Disease (a solitary red plaque with distinct borders) in that the abnormal cells are found throughout the depth of the epidermis. Acantholytic actinic keratoses have focal acantholysis (separation from other cells) occasionally accompanied by clefts. Lichenoid actinic keratoses show dense band‐like infiltration of lymphocytes in the papillary dermis and vacuolar alteration at the dermoepidermal junction. Pigmented actinic keratoses have a hyperpigmented or reticulated appearance. Differential diagnosis of actinic keratosis includes Bowen's disease, squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, seborrhoeic keratosis, and lentigo maligna (Holmes 2007).
Symptoms of actinic keratosis include tenderness, itchiness, burning, and a sandpaper‐like texture. Over time, lesions may remain unchanged, proliferate, regress, reappear, or develop into squamous cell carcinoma. Microscopically, actinic keratosis lesions show abnormal tissue development (dysplasia) in the skin cells (keratinocytes). During early development of a lesion, the lower layers of the epidermis show the most dysplastic keratinocytes. As a lesion develops, the dysplastic cells permeate the epidermis and form conical‐shaped scales when the surface of the epidermis is reached. Acceleration of growth of the epidermal layer and abnormal cellular maturation leads to excessive production of immature adherent scales with a sandpaper or gritty feel (Marks 1993). The lower skin layer (dermis) undergoes patchy inflammation as seen by an increased number of white blood cells (lymphocytes) noted in the dermis (Marks 1993).
Pathogenesis and epidemiology
The anatomical distribution of actinic keratosis lesions correlates with areas of the body that receive the most long‐term, chronic, and intense exposure to ultraviolet radiation in sunlight (Marks 1993; Schwartz 1997). More than 80% of the lesions occur on the head, neck, back of the hands, and forearms (Salasche 2000). Chronic exposure to ultraviolet (UV) radiation, mainly UVB (290 to 320 nm), is the major agent leading to mutagenesis (disordered regulation of growth) in keratinocytes (Callen 1997). In fact, mutations in the p53 tumour suppressor gene have been found in 53% of those with actinic keratoses and 69% of squamous cell carcinoma biopsies (Nelson 1994). Ultraviolet radiation can also contribute to suppression of the immune system, resulting in a decreased ability to eliminate over‐proliferating cells (Holmes 2007). Moreover, UV light could directly activate human papillomavirus replication. The virus, in turn, degrades a proapoptotic protein BAk, also preventing elimination of tumour cells (Holmes 2007). Thus, sunlight initiates and promotes the formation of non‐melanoma skin cancer.
The cause of actinic keratosis involves an interaction between skin colour (melanin protects by absorbing UVB radiation); advancing age (cumulative sun exposure and decrease in the effectiveness of the immune system); gender (actinic keratosis is more prevalent in men); history of severe sunburn in childhood; and sun exposure, which is influenced by latitude and the integrity of the ozone layer (Holmes 2007; Lebwohl 2003; Salasche 2000). Other factors may include occupation (working outdoors), socioeconomic status, and diet (Lebwohl 2003; Marks 1993; Salasche 2000; Schwartz 1997). Immunosuppressive therapy, e.g. in organ transplant recipients, and exhibition of genetic diseases of skin hypopigmentation (low pigmentation), such as xeroderma pigmentosum or albinism (Holmes 2007; Moy 2000), are also risk factors.
The first National Health and Nutrition Examination Survey (NHANES I) found that in healthy white people in the US, the age‐adjusted prevalence rate for actinic keratoses was 6.5%. This increases significantly with advancing age: In 65‐ to 74 year‐old men with high sun exposure, the prevalence rate was 55.4% and 18.5% for low sun exposure (Engel 1988). In Australia, where prevalence of actinic keratosis is the highest, as many as 40% of white adults may have an actinic keratosis. For younger adults, aged 30 to 39 years, the rate was 22% for men and 8% for women. In older adults aged 60 to 69 years, 83% of men and 64% of women have an actinic keratosis. For this population of adults, 42% developed at least 1 new lesion within the year (Frost 2000). Although known to be precancerous, the probability of a lesion undergoing malignant transformation to a squamous cell carcinoma is not clear, but ranges from 0.025% to 16% per year (Glogau 2000; Jeffes 2000).
Description of the intervention
An actinic keratosis may potentially become cancerous; therefore, monitoring is advised. Because of the prevalence of actinic keratoses among an ageing population, treatment has been sought by an increasing number of people (Warino 2006). Reasons for treatment include prevention of cancer development; relief of symptoms, such as bleeding; and improvement of cosmetic appearance. Interventions for actinic keratoses could be divided into individual treatment of lesion and field‐directed treatment, i.e. applied to an area of sun‐damaged skin where there may be multiple lesions. Individual lesion treatment (spot) might relieve symptoms or cosmetic concerns, whereas field‐directed treatment might be more appropriate for prevention of transformation into squamous cell carcinoma. Most of the field‐directed treatments are topical treatments where efficacy depends on patient compliance.
Behaviour modifications, including limiting sun exposure between 10am and 4pm, the use of sunscreens with a SPF (sun protection factor) rating of at least 15, and the use of protective clothing, are the best methods for the prevention of actinic keratosis and will help reduce the need for treatment (Schwartz 1997; Wilkerson 1984).
Various strategies for the treatment of actinic keratoses have been developed; these include physician‐administered cryotherapy for a few lesions, and topical 5‐fluorouracil, topical imiquimod, topical masoprocol, topical diclofenac in 2.5% hyaluronic acid gel, and photodynamic therapy for large numbers of lesions. Salicylic acid may also be used for early lesions, while dermabrasion and laser resurfacing are beneficial when there is coexistent photodamage or multiple recalcitrant lesions. Excision (removal of the lesion, often using a scalpel blade) and chemical peels (use of a caustic agent that causes the lesion to slough off) are both appropriate for hyperkeratotic or recalcitrant lesions. Interferon and oral retinoids are uncommon treatments, and they are still under development. These treatments have varying efficacies and adverse effect profiles (Dinehart 2000; Ibrahim 2009; Marks 1993; Wilkerson 1984).
Thus, the factors to consider when making decisions about treatment include efficacy, tolerability, number of lesions to treat, spot or field‐directed treatment, compliance, history of skin cancer, immunosuppression, previous treatment history, and cosmetic appearance.
How the intervention might work
Topical Interventions
Diclofenac gel
One topical treatment for actinic keratoses is the non‐steroidal anti‐inflammatory drug (NSAID) diclofenac in 2.5% hyaluronic acid gel. The hyaluronic acid vehicle contributes to the success of this treatment by delivering and then retaining diclofenac at the epidermis, protecting against UV radiation and its cosmetic properties (Brown 2005). Although the precise mechanisms of action are not clear, diclofenac is thought to target several aspects of actinic keratosis pathophysiology. One mechanism that has been proposed is the inhibition of cyclooxygenase 2 (COX‐2) (Hemmi 2002), which leads to a reduction in prostaglandin synthesis (Rivers 2004). This COX‐2 inhibition or other mechanisms may be responsible for diclofenac’s inhibition of cell differentiation in vitro, induction of apoptosis in vitro and in vivo, alteration of cell proliferation, and inhibition of angiogenesis (Adamson 2002; Alam 1995; Lu 1995; Seed 1997). Diclofenac has also been shown to activate the nuclear hormone receptors, peroxisome proliferator‐activated receptors (PPARs), in vitro; these receptors are involved in many cellular functions including cell differentiation and apoptosis (Adamson 2002).
5‐Fluorouracil (5‐FU)
This topical agent causes a decrease in cell proliferation and an induction of cell death, particularly in cells with high mitotic (cell division) rates. This occurs through the inhibition of thymidylate synthetase, which blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby, interfering with DNA and RNA synthesis (Berman 2006; Chakrabarty 2004; Eaglstein 1970; Robins 2002b).
Imiquimod
This topical treatment for actinic keratoses is a synthetic compound belonging to the imidazoquinolone family of drugs (Hemmi 2002). It acts as an immune modulator by activating toll‐like receptors, ultimately resulting in the modulation of the mRNA expression of many immunomodulatory genes, which induces the production of cytokines by monocytes, macrophages, and epidermal keratinocytes (Correale 2002; Stanley 1999). This has the effect of enhancing innate and acquired immune responses, which leads to strong antiviral and antitumoural activity (Vidal 2006). Imiquimod also induces pro‐apoptotic pathways through a variety of mechanisms (Amini 2010).
Chemical Interventions
Cryotherapy
Cryotherapy is often the treatment of choice for individual actinic keratosis lesions (Goldberg 2010). It uses liquid nitrogen to freeze and destroy the epidermis containing actinic keratoses (Goldberg 2010), with efficacy increasing as a function of freezing duration (Thai 2004).
Photodynamic therapy (PDT)
Photodynamic therapy involves the selective accumulation of a photosensitising agent in premalignant or malignant cells (Gold 2008; Juarranz 2008). This is achieved by the application of 5‐aminolevulinic acid (5‐ALA) or MAL (ALA methyl ester), which are precursors to protoporphyrin IX (PpIX), a potent photosensitiser (Fink‐Puches 1997). This causes an excess of PpIX, which selectively accumulates in neoplastic cells. Subsequently, the photosensitiser is activated by visible light, causing the generation of reactive oxygen species in the presence of oxygen. These reactive oxygen species [mainly singlet oxygen (ˈO₂)] start a cascade of biochemical events that induce damage and the death of neoplastic cells through an apoptotic mechanism (Juzeniene 2007; Moan 1991).
Why it is important to do this review
The existing evidence for use of the various treatment agents for actinic keratoses is varied, and there are concerns regarding adverse events and cosmetic outcomes. It is vital to critically assess data in terms of the benefits as well as the risks associated with treatment.
Objectives
To assess the effects of interventions for actinic keratoses.
Methods
Criteria for considering studies for this review
Types of studies
This review included randomised controlled trials comparing the treatment of actinic keratoses to either placebo, vehicle, other current therapies, or variation in treatment conditions (e.g. different concentrations of the active ingredient or types of light sources for phototherapy). We included cross‐over trials and parallel and intraindividual (e.g. left‐ or right‐side comparison) studies.
Types of participants
We included participants with clinical signs of actinic keratoses as assessed by a medical practitioner or histological diagnosis. Diagnostic criteria, such as the Marks definition (Marks 1993) or the Salasche or Schwartz characterisation (Salasche 2000; Schwartz 1997), were acceptable, as was the diagnosis of actinic keratoses by a dermatologist using the terms 'actinic keratosis', 'solar keratosis', 'senile keratosis', 'senile hyperkeratosis', 'keratoma senile', or 'keratosis senilis'. We included studies with immunocompetent and immunosuppressed participants.
Types of interventions
We considered the following interventions:
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prescription‐based topical treatments, e.g. diclofenac in hyaluronic gel, 5‐fluorouracil, or imiquimod;
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prescription‐based oral drugs, e.g. oral retinoids;
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mechanical interventions, e.g. curettage, dermabrasion, or resurfacing;
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chemical interventions, e.g. chemical peels, cryotherapy, or photodynamic therapy; and
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combinations of topical and oral treatments with mechanical or chemical interventions.
The comparators were vehicle, placebo, another active compound or intervention, or a variation of the treatment (duration, concentration, etc).
Types of outcome measures
For actinic keratoses, the outcomes can be expressed per lesion or per participant. Because the participants or body parts of the participants (intraindividual design), not the lesions, were generally randomised, only per‐participant outcomes could be included in meta‐analyses. Thus, the included outcomes in this review were outcomes reported per participant.
Efficacy outcomes for studies on actinic keratoses are generally based on the clearance of individual lesions. Lesions present at baseline are generally identified, graded (grade I: slightly palpable, better felt than seen; grade II: moderately thick, easily seen and felt; and grade 3: very thick, hyperkeratotic, or both), and mapped. Use of transparencies and photography might help with this process. Sometimes distinction is made between lesions present at the baseline and new lesions appearing during the study. At the end of the study, the assessors evaluate the clearance, or not, of the lesions.
Ideally, complete clearance of actinic keratosis lesions at follow‐up would be measured (i.e. number of participants with 100% clearance of target (present at baseline) or all actinic keratosis lesions).
A second outcome measurement, such as partial clearance, is also often used. The definition of partial clearance is subjective but frequently indicates the number of participants with 75% or more of actinic keratosis lesions being completely cleared, i.e. a reduction in the number of lesions by at least 75%.
Alternatively, the mean reduction of total number of lesions at baseline per participant is also used, i.e. the difference between the mean number of lesions at baseline and the mean number of lesions at assessment. The results are then presented as absolute mean or mean percentage of reduction in lesion counts compared to baseline.
We only included outcomes expressed as number of participants experiencing adverse events in this review.
Cosmetic outcomes are really varied from global assessment to individual characteristics, such as changes in pigmentation. We only included outcomes expressed as number of participants or mean per participant in this review.
Primary outcomes
Efficacy outcomes
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Subjective assessment: global degree of improvement in symptoms or signs as rated by a medical practitioner or participant, or global improvement indices (GII) for completely improved or cleared.
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Objective assessment: participant complete (100%) or partial (> 75%) clearance.
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Objective assessment: mean reduction in lesion counts (absolute number or percentage).
Secondary outcomes
Safety and cosmetic outcomes
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Withdrawal due to adverse events.
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Skin irritation.
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Minor adverse events excluding skin irritation.
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Cosmetic outcomes: cosmetic changes, including pigmentation and scarring.
Search methods for identification of studies
We aimed to identify all relevant randomised controlled trials (RCTs) regardless of language or publication status (published, unpublished, in press, and in progress).
Electronic searches
We searched the following databases up to 23 March 2011:
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the Cochrane Skin Group Specialised Register using the terms: ((actinic or solar or senile) and keratos*) or hyperkeratos*;
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the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library using the search strategy in Appendix 1:
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PUBMED/MEDLINE via OVID (from 2005) using the strategy in Appendix 2;
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EMBASE via OVID (from 2010) using the strategy in Appendix 3; and
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LILACS (Latin American and Caribbean Health Science Information database, from 1982) using the strategy in Appendix 4.
The UK and US Cochrane Centres have an ongoing project to systematically search MEDLINE and EMBASE for reports of trials, which are then included in the Cochrane Central Register of Controlled Trials. Searching has currently been completed in MEDLINE from inception to 2004 and in EMBASE from inception to 2009. Further searches of these two databases were undertaken for this review by the Cochrane Skin Group to cover the years not searched by the UK and US Cochrane Centres for CENTRAL.
A final prepublication search for this review was undertaken on 4 April 2012. Although it has not been possible to incorporate RCTs identified through this search within this review, relevant references are listed under 'Studies awaiting classification'. They will be incorporated into the next update of the review.
Trials Registers
We searched the following trials registers on 10 March 2011 using the search terms ((actinic, senile, or solar) and keratos) or hyperkeratos.
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The metaRegister of Controlled Trials (www.controlled‐trials.com).
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The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).
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The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).
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The World Health Organisation International Clinical Trials Registry platform (www.who.int/trialsearch).
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The Ongoing Skin Trials Register (www.nottingham.ac.uk/ongoingskintrials).
Searching other resources
Unpublished literature
We conducted online searches (via pharmaceutical company websites, the U.S. Food and Drug Administration (FDA) website, or both) for the following products and drug companies:
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3M/Graceway Pharmaceuticals (imiquimod, Aldara, or Zyclara);
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Actavis Mid‐Atlantic LLC (imiquimod);
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Allergan (5‐fluorouracil, Fluoroplex);
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Apotex (imiquimod);
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Dermik/Sanofi Aventis (5‐fluorouracil, Carac);
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DUSA Pharmaceuticals (aminolevulinic acid, Levulan Kerastick);
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Galderma (adapelene, Differin);
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ICN (5‐fluorouracil, Efudex);
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Leo Pharmaceuticals (calcipotriol, Dovonex, or Daivonex);
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Mochida Pharmaceuticals (imiquimod, Beselna);
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PharmaDerm/NycoMed US (diclofenac, Solaraze);
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Pharmacia & Upjohn (5‐fluorouracil);
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Photocure ASA/Galderma (methyl aminolevulinate, Metvix, or Metvixia);
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Roche (etretinate, Tegison);
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Stiefel/GlaxoSmithKline (isotretinoin, Isotrex, or Isotrexin); and
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URL Pharma (colchicine, Colcrys).
Conference proceedings
We scanned the conference proceedings of the British Association of Dermatologists and the European Academy of Dermatology from 2007 to 2011 for further references to relevant trials. We examined the conference proceedings for 2009 and 2010 of the Annual Meeting of the American Academy of Dermatology, the Annual Meeting of the European Society for Dermatological Research, the Congress of the European Association of Dermatol‐Oncology, the Annual Meeting of the British Association of Dermatologists, and the Annual Meeting of the Australasian College of Dermatologists. We scanned the conference proceedings for the 2012 Annual meeting of the American Academy of Dermatology.
Language restrictions
We imposed no language restrictions when we searched for publications. We electronically translated articles published in languages other than English.
Adverse effects
We did not perform a separate search for adverse effects of interventions for actinic keratoses. We looked at reports of adverse events or side‐effects in the RCTs identified as a result of our searches, as part of our secondary outcomes.
Data collection and analysis
Selection of studies
At least two authors (WB and MP) independently checked titles and abstracts identified from the searches. We obtained the full text of all studies of possible relevance for independent assessment by two authors (MP and WB). The authors decided which trials fit the inclusion criteria and recorded their methodological quality (MP and WB). They resolved any disagreement by discussion between the authors and a third party arbitrator (AG). Previous contributors also participated in this process in earlier versions of the review.
Data extraction and management
At least two authors extracted and summarised, using data collection forms, the details of eligible trials. One author (MP) double‐checked and entered data. The authors were not blinded to the names of the trial authors, journals, or institutions.
Assessment of risk of bias in included studies
Assessment of risk of bias included the Review Manager 5.1 'Risk of bias' assessment tool shown in the 'Risk of bias' tables. In addition, GradePro "quality of evidence" was also used for selected outcomes, and the results are shown in the overview tables for five selected interventions.
Measures of treatment effect
We performed a meta‐analysis for each treatment comparison to calculate a weighted treatment effect across trials. We expressed the results as a risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes, and a mean difference (MD) with 95% CI for continuous outcomes. We calculated the number needed to treat (NNT) for significantly different dichotomous outcomes using the following formula: NNT = Ι 1/ ACR * (1‐RR)Ι where the risk ratios (RR) from the meta‐analysis and the moderate assumed control risk (ACR) calculated in GRADEpro was used. For ACR, a mean baseline risk from the study was used for analysis with only one study; and low, median, or high control‐group risk were used based on the variation in the included studies in meta‐analysis. This previous method would not be applicable to outcomes with an ACR of 0%, i.e. no event in the control group, because of the numerical problems that would ensue.
Unit of analysis issues
The unit of analysis was the participant. We analysed cross‐over trials using data from the first phase only and pooled, where possible, with parallel‐design studies. We divided results from withinparticipant trials (intraindividual, e.g. split face) into 2 categories: 1) outcomes expressed as number of participants (e.g. participant complete clearance), which could not be included in meta‐analyses, were only reported in the text; and 2) outcomes expressed as mean with standard deviation (e.g. mean reduction in lesion counts = mean of reductions observed in each participant), which could be included in meta‐analyses using the inverse‐variance method. We combined together data from studies with multiple treatments when appropriate (e.g. "all treatment groups" versus "placebo"), or we split the data from the shared group. If studies were using more than one outcome included in this review, we included all outcomes in the analyses.
Assessment of heterogeneity
We assessed heterogeneity using an I² statistic value expressed as a percentage. We excluded results from meta‐analyses with an I² statistic value of 80% or higher. We explored reasons for heterogeneity in studies, and if necessary, sensitivity analyses examined the effects of excluding a study, e.g. those studies with lower methodological quality.
Many studies do not distinguish between the physical location of actinic keratosis lesions on the body. This can introduce heterogeneity, as actinic keratoses of the face and scalp are often more effectively treated by certain topical formulations than lesions located elsewhere. In some studies, pretreatment of lesions to remove hyperkeratosis essentially negated the differences encountered by lesion location, as lower response has been associated with greater hyperkeratosis. Most of the studies included limited their investigation to grade one or two lesions, i.e. minimally to moderate thick lesions. However, when comparing efficacy results from two separate studies using the same treatment, studies incorporating pretreatment of any kind may have accounted for different efficacy rates.
Data synthesis
A random‐effects model was prespecified for all meta‐analyses. The Mantel‐Haenszel method was used for dichotomous outcomes (e.g. cure rates), and an inverse variance model was used for continuous outcomes (e.g. mean reduction in lesion counts).
Subgroup analysis and investigation of heterogeneity
Where appropriate, we undertook subgroup analysis (subgroups of participants) in an attempt to decrease heterogeneity between studies (for example, when different dosing regimens were used or to keep information separated, i.e. when blue or red light was used for photodynamic therapy). In addition, if data were presented for several assessment time points or anatomical locations, we performed subgroup analyses.
Results
Description of studies
See the 'Characteristics of included studies', 'Characteristics of excluded studies', and 'Characteristics of ongoing studies'.
Results of the search
We identified 1001 references from searching bibliographic and trials databases, as well as 28 references through other sources. After removing duplicate references and ongoing studies without results, we had 469 records to screen. We excluded 318 records based on titles and abstracts as they did not meet our eligibility criteria (non‐randomised studies, reviews, not interventions to cure). We assessed the full texts of the remaining 151 records. We then excluded a further 55 records, leaving 96 studies. We included 83 of these in our qualitative analysis; 12 are listed under studies awaiting classification, and 1 is an ongoing study. We included 75 studies in our meta‐analysis.
The PRISMA study flow chart in Figure 1 summarises the results of the search for studies.
Study flow diagram.
(Please note that in all tables in the results section, the "X" means that the associated outcome was reported, and when there was no participant withdrawal it is specified between parentheses.)
Included studies
We included 83 randomised studies in the review, encompassing 10,036 participants in total.
Design
We only included the randomised (participants or right/left side in intraindividual studies) clinical trials if the interventions were covered by this review and if they reported numerical results for at least one of the review outcomes. This criterion excluded the outcome 'withdrawal due to adverse events', which is generally reported in all studies.
Some studies had more than one design. The design of the studies is summarised in the following table.
| Placebo/vehicle‐controlled | Active‐ controlled1 | |
| Parallel groups | 46 studies (including part I of 1 cross‐over study) | 17 studies |
| Intraindividual2 | 12 studies | 10 studies |
1. Active‐controlled = compared to another treatment, which could be a different treatment or the same treatment at a different concentration, duration, or types of light used for photodynamic therapy.
2. Intraindividual = within‐patients, i.e. different body parts of the same participant received different treatments in parallel (not sequentially).
Sample sizes
Studies ranged in sample size from 4 to 492 participants (124 + 127, mean + SD).
Interventions
The interventions assessed in the studies included the following.
Topical treatments
-
Adapalene gel
-
Aretinoid methyl sulfone (Ro 14‐9706)
-
Betulin‐based oleogel
-
Calcipotriol (vitamin D)
-
Colchicine
-
Diclofenac
-
2‐(Difluoromethyl)‐dl‐ornithine (DFMO)
-
5‐fluorouracil (5‐FU)
-
ß‐1,3‐D‐glucan
-
Imiquimod
-
Ingenol mebutate (PEP005)
-
Isotretinoin
-
Masoprocol
-
Nicotinamide
-
Resiquimod
-
Sunscreen
-
DL‐α‐tocopherol (vitamin E)
-
Tretinoin
A total of 60 studies investigated topical treatments.
Oral treatments
-
Etretinate
One study investigated oral treatment.
Mechanical interventions
-
Resurfacing (carbon dioxide and Er:YAG lasers)
Two studies investigated mechanical interventions.
Chemical interventions
-
Cryotherapy
-
Photodynamic therapy (using a variety of different parameters)
-
Chemical peel (trichloroacetic acid)
A total of 37 studies investigated chemical interventions.
Interventions in the included studies could also be segregated based on clinical (e.g. PDT or cryotherapy) or participant (e.g. topical cream) administration, as well as treatments for individual lesions (e.g. cryotherapy) or field‐directed treatments (e.g. topical cream).
Participants
Participants in the studies were generally in good health, but a few studies specifically recruited participants with a history of non‐melanoma skin cancer. We included studies with organ transplant recipients (immunosuppressed), but these were analysed separately. Responsiveness to immunomodulators may decrease with increasing age, so the age of participants might influence the efficacy of treatments using them. In the included studies, most of the participants were men with mean ages of 60 to 70 years. Lesions were generally grade I (slightly palpable, better felt than seen) or II (moderately thick, easily seen and felt). The location of actinic keratosis lesions, i.e. lesions difficult to access for cream application, could also influence participant compliance and ultimately the efficacy of participant‐administered treatments. Lesions were located on the head only (i.e. face, forehead, temples, cheeks, scalp, ear, lips, and neck) in 59 studies, on only non‐head locations (upper and lower extremities, legs, arms, elbow, forearms, hands, dorsa of hands, shoulder, décolleté, chest, trunk, and back) in 9 studies, and on both head and non‐head locations (including the term "other") in 22 studies. One study did not specify the location of the lesions. In general, lesions were more often located on the face and scalp, which are easy to reach.
Outcomes
Efficacy outcomes
The included studies reported several efficacy outcomes. A lot of the studies did not specify if only target (baseline) lesions or all lesions [i.e. target and subclinical lesions (new lesions appearing during the study)] were included in their analysis. Most of the studies reported more than one outcome. Some of these outcomes corresponded to our primary outcomes or could be transformed into our primary outcomes, whereas others did not meet our criteria for this review. We have summarised the primary and other outcomes in the following table.
| Number of studies | Outcomes | Equivalence or transformed into outcome |
| Primary outcomes | ||
| 12 | Global improvement indices expressed per participant (Investigator, participant, or both) | Physician global assessment improvement, global therapeutic response or treated area, investigator assessment scale, investigator global assessment, overall response |
| 53 | Participant complete clearance (number of participants, rate, proportion, percentages) | Complete responders, total clearance, response to treatment, proportion of participants achieving total clearance, field complete clearance, complete remission, complete response of lesional area, participant's complete resolution, complete clearing, number of participants with 100% clearance, complete participant response, target lesion number score = 0, complete healing, cumulative lesion number score = 0, 100% lesions cleared, percentage of participants who experienced 100% clearance of all target lesions, number of participants with all cleared lesions |
| 20 | Participant partial (> 75%) clearance (number of participants, rate, proportion, percentages) | At least 75% reduction in the number of lesions, at least 75% of lesions cleared, percentage of participants who experienced 75% or greater clearance of all target lesions, therapy responders with at least 75% of clearing of the lesions, participant partial (> 80%) clearance rates |
| 50 | Mean reduction in lesion counts (absolute values or percentages) | Mean reduction in the number of actinic keratoses, mean changes of lesion counts, mean numbers of lesions at baseline and assessment time point, mean percentage reduction in the number of actinic keratoses, average changes in lesion counts, mean per cent changes from baseline for all actinic keratoses, mean per cent lesions cleared |
| Other outcomes | ||
| 3 | Global improvement indices expressed as scores | Physician global assessment, global improvement score |
| 29 | Lesion complete response (per lesions) | Reduction rate in number of actinic keratoses, clearance of individual lesions, rate of totally healed lesions, number of lesions with 0% of remaining area, complete clinical clearance rate on lesion basis, complete clearance rate of lesions, individual lesion clearance, lesion counts at baseline and assessment, percentage lesion reduction, proportion of baseline lesions cleared at the end of treatment, lesions remitted, total lesion counts |
| 9 | Median per cent reduction of baseline lesions | Median per cent changes from baseline for all actinic keratoses |
| 6 | Participant histological clearance | Histological clearance, histological confirmation |
| 5 | Recurrence | ‐ |
| 3 | Participant partial (> 50%) clearance | Participant with 50% or greater reduction, clearance = resolution of > 50% of the lesions |
| 5 | Reduction in lesion size | Overall reduction in lesion area, partial remission (50% size reduction of 75% of lesions), mean diameter of target lesion at baseline and assessment |
| 2 | Median number of lesions at baseline and assessment time point | ‐ |
| 1 | Participant partial (> 66%) clearance | ‐ |
| 1 | Participant partial (% not specified) clearance | ‐ |
| 1 | Total lesion number score (0 = 0 lesions, 1 = 1 to 3 lesions, 2 = 2 to 4 lesions, 3 = > 6 lesions) | ‐ |
| 1 | Negative predictive value, i.e. ratio between histological and clinical clearance | ‐ |
| 1 | Participant's perception of efficacy | ‐ |
| 1 | Efficacy on a visual analogue scale for field‐directed treatment | ‐ |
| 1 | Relapse | ‐ |
Safety outcomes
There was a lot of variability in the safety outcomes reported by the included studies. Some studies provided briefly qualitative observations on adverse events, whereas others gave detailed quantitative description of adverse events. Intraparticipant studies have limitations in assessing adverse events other than application site and local skin reactions. Adverse events might influence a participant's compliance as well as the maintenance of the blinding. In turn, poor compliance and unblinding could compromise the evaluation of the treatment efficacy. Moreover, adverse events are an important factor in a physician's decision about appropriate treatment for their patients, and a more standardised report of adverse events would be beneficial. The safety outcomes that were our prespecified secondary outcomes found in the included studies, as well as other outcomes, are summarised in the following table.
| Number of studies | Outcomes | Equivalence or transformed into outcome |
| Secondary outcomes | ||
| 77 | Withdrawal due to adverse events | None lost = all participants completed the trial/study, or lost participants were all justified by other reasons |
| 15 | Skin irritation (per participant) | Application site irritation, local irritation, facial irritation, graphical representation of irritation, number of participants reporting relative irritation between treatments |
| 31 | Minor adverse events excluding skin irritation (number or percentages of participants) | Most frequent adverse events, number of participants reporting individual adverse events, participants with eye irritation, percentages of participants reporting adverse events for only 1 treatment arm or pooled data, specific treatment‐related adverse events |
| Other outcomes | ||
| 16 | Application site reactions in general (number or percentages of participants experiencing reactions in general) | Adverse events at treatment sites |
| 15 | Application site reactions for specific reactions (number or percentages of participants experiencing specific reactions) | Adverse events at treatment sites |
| All = 6 Severe = 3 | Local skin/adverse reactions ‐ in general (number of percentages of participants) | Local adverse events |
| All = 33 Severe = 12 | Local skin/adverse reactions for specific reactions (number of percentages of participants) | Local skin reactions reported for only 1 treatment arm or pooled data, graphical representation of local skin reactions |
| 20 | Participants experiencing at least 1 adverse event (number or percentages of participants) | Number or percentage of participants reporting adverse events, graphical representation of percentages of participants experiencing adverse events |
| 11 | Treatment‐related adverse events in general (number or percentages of participants) | ‐ |
| 31 | Serious adverse events (treatment‐related or not) | ‐ |
| 6 | Serious adverse events‐detection of basal cell carcinoma (presence or not per participant) | ‐ |
| 7 | Serious adverse events ‐ detection of squamous cell carcinoma (presence or not per participant) | ‐ |
| 24 | Clinical laboratory tests | ‐ |
| 2 | Incidences of application site reactions (number of events) | ‐ |
| 1 | Application site reactions reported per lesions | ‐ |
| 18 | Local tolerability (severe, moderate, mild, absent) | Severity of local skin reactions, global severity rating of local reactions, side‐effects (skin reactions) on a scale, irritation severity, severity of facial irritation, severity of local adverse events, grading of individual local reactions, physician's grading of erythema |
| 2 | Number of reports of skin irritations | Incidence of local skin reactions |
| 2 | Number of participants with strong, moderate, weak, or no inflammatory reaction | ‐ |
| 1 | Local phototoxic reactions | ‐ |
| 2 | Number of treatment‐related adverse events (incidence) | ‐ |
| 1 | Qualitative report on treatment‐related adverse events | ‐ |
| 22 | Qualitative report on skin irritation (types and severity) | Comparison of severity of adverse events between treatments |
| 5 | Number of reports of adverse events (incidences) | ‐ |
| 1 | Number of reports of serious adverse events | ‐ |
| 12 | New actinic keratosis lesions | Subclinical lesions, increase in number of lesions during the study |
| 7 | Pain score | Mean visual analogue scale for pain |
| 2 | Skin discomfort on a visual analogue scale | ‐ |
| 1 | Duration of discomfort | ‐ |
| 1 | Erythema measured by skin reflectance meter | ‐ |
| 1 | Graft rejection (organ transplant participants) | ‐ |
| 1 | Detection of Bowen's disease | ‐ |
| 1 | Incidence of new non‐melanoma skin cancer | ‐ |
The evaluation of the 'skin irritation' outcome was restricted, as only 15 studies had outcomes containing explicitly the term 'irritation'. Several studies reported application site, local skin reactions, or both, which generally included signs and symptoms of skin irritation, such as burning/stinging, erythema, oedema, pruritus, and scaling. We could have included these skin irritation signs and symptoms as more specific 'skin irritation' outcomes if a universal definition of skin irritation existed. Because of the exclusion of skin irritation in the 'minor adverse events' outcome, these reactions as well as the number of participants reporting at least one adverse event, related or not to the treatment (which could include skin irritation), could not be included in any of our secondary outcomes.
Cosmetic outcomes
Only a few studies reported cosmetic outcomes and were varied. In general, cosmetic evaluation was performed on cleared lesions. The cosmetic outcomes that were our prespecified secondary outcomes found in the included studies, as well as other outcomes, are summarised in the following table.
| Number of studies | Outcomes | Equivalence or transformed into outcome |
| Cosmetic outcomes reported per participant | ||
| 4 | Changes in pigmentation | Hypopigmentation, hyperpigmentation |
| 3 | Global cosmetic outcome of "good", "very good", or "excellent" | Final cosmetic results, overall cosmetic outcome |
| 2 | Cosmetic appearance score | Total score for cosmetic appearance (erythema, desquamation, induration), cosmetic appearance scores by participant and investigator on a 7‐point scale (‐3 = much worse to +3 = much better) |
| 4 | Skin quality | Decrease in roughness/dryness/scaliness of the skin, normal skin surface, decrease of scarring |
| 4 | Improvement in photodamage or photoageing score | Investigator global integrated photodamage, photodamage score (fine lines, mottled pigmentation, tactile roughness, sallowness), photoageing score (global appearance, fine wrinkles, mottled hyperpigmentation, coarse wrinkles, rosy glow) |
| 2 | Significantly ‐ or much‐ improved cosmetic outcome | ‐ |
| 1 | Decreased infiltration and disappearance of crust | ‐ |
| 1 | Proportion of participants with improvement of surface with actinic damage | Note: the number of participants was not given and could not be included in the analysis |
| Other outcomes | ||
| 5 | Cosmetic outcomes per cleared lesions | ‐ |
| 2 | Total thickness score | ‐ |
| 1 | Changes in pigmentation per lesions | ‐ |
Other outcomes
The studies sometimes reported additional outcomes, and they are summarised in the following table. They rarely reported important outcomes, such as compliance, (7 studies) compared to the number of studies investigating participant‐administered treatments (63 studies, including 3 daylight photodynamic therapy studies).
| Number of studies | Outcomes |
| 10 | Participant's satisfaction |
| 8 | Rest periods or temporary interruption during treatment |
| 7 | Compliance |
| 6 | Participant's preference |
| 2 | Biological and immunological outcomes |
| 1 | Skin concentrations of drug and products due to its mechanism of action |
| 1 | Investigator's preference |
| 1 | Lesion severity index |
| 1 | Quality of life on a visual analogue scale |
| 1 | Number of spray cooling for photodynamic therapy |
In 2011, we contacted the following authors to get clarification on the studies included.
| Author | Topic | Clarification |
| Kurt Gebauer | Type of analysis used in the study Gebauer 2003 | Intention‐to‐treat |
| Joseph Jorizzo | Type of analysis used in the studies Jorizzo 2002 and Jorizzo 2006 | The type of analysis could not be confirmed |
| Iraji Fariba | Outcome presented was 'lesions complete response' or 'participant complete clearance' in the study Fariba 2006 | No response received |
| Emil Tanghetti | Type of analysis used in the study Tanghetti 2007 | Intention‐to‐treat |
Excluded studies
Generally, we excluded studies if they were not randomised clinical trials on interventions to cure actinic keratosis lesions (actinic keratoses). In addition, we excluded some randomised studies for the reasons cited in the tables of excluded studies in the 'Characteristics of excluded studies' section. The following table summarises the main reasons for the exclusion of these studies.
| Data not separated for actinic keratoses | Did not meet review criteria for outcomes | Unacceptable or unclear randomisation | No numerical values, graphical data, or not enough information | Prevention of actinic keratosis lesions | Follow‐up reports on included studies |
In 2011, we tried to contact the following author to get clarification on the studies excluded.
| Author | Topic | Clarification |
| Barbara A. Gilchrest | 1) Number of treatment arms and number of participants allocated 2) Mean numbers of lesions and their standard error of the mean (SEM) for the 3 groups, i.e. 1, 2, and 3 hours | 1) 3 groups of 6 participants each incubated for 1, 2, or 3 hours 2) not received |
Risk of bias in included studies
Please refer to the 'Risk of bias' tables for each included study, which are part of the 'Characteristics of included studies' tables, and the summary figure, Figure 2 ('Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Ffity studies were judged to be at low risk of bias with regard to the method used to generate the randomisation sequence, which were stratification (Alberts 2000; Foote 2009; Freeman 2003; Hauschild 2009a; Hauschild 2009b; Pariser 2003; Pariser 2008; Szeimies 2002; Thompson 1993), computer‐generated randomisation schedule (Gebauer 2009; Huyke 2009; Jorizzo 2004; Jorizzo 2006; Jorizzo 2010; Korman 2005; Lebwohl 2004; Loven 2002; Ooi 2006; Ostertag 2006; Szeimies 2004; Szeimies 2009; Szeimies 2010b; Wiegell 2011a), permuted block randomisation (Anderson 2009; Chen 2003; Kang 2003; McEwan 1997; Moloney 2010; Szeimies 2008; Wiegell 2011a), shuffling of envelopes or drawing of lots (Wiegell 2008; Wiegell 2009), and random digits table or number generator (Seckin 2009; Shaffelburg 2009).
Only 16 studies stated the methods used for allocation concealment before the treatments were assigned, and we judged these studies at low risk of bias. Eight studies used opaque sealed envelopes (Chen 2003; Freeman 2003; Moloney 2010; Szeimies 2004; Tarstedt 2005; Wiegell 2008; Wiegell 2009; Wiegell 2011a). Two studies assigned the next sequential number (Korman 2005; Shaffelburg 2009). An external person (pharmacist, sponsor, or CRO) handled the randomisation process in six studies (Krawtchenko 2007; Pariser 2008; Siller 2009; Stockfleth 2002; Swanson 2010a; Van der Geer 2009).
Blinding
Double‐blind or assessor‐blind were used in 58 and 10 studies, respectively. Nine studies were open. In some of these studies, blinding was difficult because of the nature of the treatments being compared (e.g. surgical treatment versus topical treatment). Some authors also reported that adverse events, such as the local skin reactions associated with some treatments, might have compromised the blinding. In these cases, different investigators could have been involved in the treatment/safety assessment and the efficacy assessment in order to keep the part of the assessment blinded. Additionally, the use of photography in the evaluation process could help to keep the assessor blinded. The evaluation of the risk of bias for participants, personnel and assessors took into consideration the type of blinding, and when possible, the possibility of unblinding. Of our 83 included studies, we judged 48 as at low risk of bias for both these domains, 19 studies, at high risk of bias, and 3, as unclear for both domains.
Incomplete outcome data
Three studies used intention‐to‐treat (ITT) analyses, and 25 studies used per‐protocol (PP) analyses. Nine studies used both types of analysis. The type of analysis was undetermined in 12 studies. Most studies adequately recorded characteristics of participants not completing the study. We considered studies where < 20% of enrolled participants dropped out as acceptable, and only three studies (Alirezai 1994; Persaud 2002; Zeichner 2009) exceeded 20%. For the meta‐analyses, we favoured data from ITT analyses over PP analyses, and we converted PP data to ITT data when possible. The evaluation of the risk of bias took into consideration the type of analysis, the number of dropouts, if the reasons for the dropouts were given, and possible discrepancy in the data presented.
Selective reporting
We judged 14 studies as at low risk of bias based on the following criteria: 1) The study protocols were available, and all the prespecified outcomes were presented; 2) the same data were presented in different formats (abstract, protocol with data, product insert, and published report); or 3) non‐significant outcomes were reported.
We judged 42 studies as at high risk of bias based on the following criteria: 1) Not all prespecified outcomes in the protocol or methods section were presented (e.g. the percentage in mean reduction in lesion counts was stated, but only absolute counts were presented); or 2) when the outcomes were incompletely reported and could not be entered in meta‐analysis (e.g. the standard deviations associated with mean reduction in lesion counts were not reported and the statistical significance between treatments was impossible to determine). We encountered this last example frequently. A few studies only gave data for only one treatment arm or pooled together for different treatment arms. For example, they did not always report adverse events separately for the different treatments. Of course, separate reports were impossible for studies using intraindividual study design.
Twenty‐seven studies reported unclear risk of bias. We refer the readers to the 'Risk of bias' tables for each included study for additional information on possible publication bias.
Effects of interventions
We presented the data and analyses of the included studies in two sections.
A) Overviews of the results with five selected outcomes (three primary and two secondary outcomes) expressed as comparative risks and risk ratios (RR) for five selected interventions in immunocompetent participants.
B) Results expressed as risk ratios (RR), number needed to treat (NNT), and mean difference (MD) presented for all interventions and all reported primary and secondary outcomes.
A) Overviews of selected interventions
Because of the variety of data presented for the different outcomes, we made a selection based on the data most frequently presented. For example, 'participant complete clearance' has been reported for target, subclinical, and all lesions, but most of the included studies reported data for all lesions. Thus, to be able to compare the different treatments and keep the summary table simple, we only included 'participant complete clearance' for all lesions. When data were presented for different cycles of treatments, only data for one cycle were included. Selections specific for one treatment are described in the comments section of the overview tables.
Diclofenac in 2.5% hyaluronic acid
Table 1 is an overview for 3% diclofenac in 2.5% hyaluronic acid.
| Diclofenac in 2.5% hyaluronic acid compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk With comparator | Corresponding risk With intervention | |||||
| Participant complete clearance | ||||||
| 3% diclofenac in 2.5% hyaluronic acid/2.5% hyaluronic acid | Study population | RR 2.46 | 420 | ⊕⊕⊕⊝ | For all lesions, data from 30, 60, and 90 day treatments pooled together, assessment at 30 days after the end of treatment (Analysis 6.5) | |
| 127 per 1000 | 313 per 1000 | |||||
| Moderate | ||||||
| 132 per 1000 | 325 per 1000 | |||||
| 3% diclofenac in 2.5% hyaluronic acid/5% imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT/2.5% hyaluronic acid + ALA‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean reduction in lesion counts | ||||||
| 3% diclofenac in 2.5% hyaluronic acid/2.5% hyaluronic acid | The mean reduction in lesion counts in the control groups was | The mean reduction of lesion counts in the intervention groups was | ‐ | 345 | ⊕⊕⊕⊕ | Data from 30, 60, and 90 day treatments pooled together, assessment 30 days after the end of treatment (Analysis 6.12) |
| 3% diclofenac in 2.5% hyaluronic acid/ 5% imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT/2.5% hyaluronic acid + ALA‐red light PDT | See comment | See comment | Not estimable | 10 | ⊕⊕⊝⊝ | Intraindividual study: at 6 weeks; diclofenac/hyaluronic acid (HA) + ALA‐PDT = 10.13, HA + ALA‐PDT= 9.9, at 6 months; diclofenac/HA + ALA‐PDT = 11.56, HA + ALA‐PDT = 10.56, at 12 months; diclofenac/HA + ALA‐PDT = 12.5, HA + ALA‐PDT = 8.8 |
| Mean percentage of reduction in lesion counts | ||||||
| All comparisons | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Withdrawal due to adverse events | ||||||
| 3% diclofenac in 2.5% hyaluronic acid/2.5% hyaluronic acid | Study population | RR 3.59 | 592 | ⊕⊕⊕⊕ | Additional data from intraindividual study: no participant withdrew because of adverse events (N = 20). GRADE = low. | |
| 40 per 1000 | 144 per 1000 | |||||
| Moderate | ||||||
| 43 per 1000 | 154 per 1000 | |||||
| 3% diclofenac in 2.5% hyaluronic acid/5% imiquimod | 0 per 1000 | 0 per 1000 | Not estimable | 49 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT/2.5% hyaluronic acid + ALA‐red light PDT | 0 per 1000 | 0 per 1000 | Not estimable | 10 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Skin irritation | ||||||
| 3% diclofenac in 2.5% hyaluronic acid/2.5% hyaluronic acid | See comment | See comment | Not estimable | 20 | ⊕⊕⊝⊝ | Intraindividual study reported irritation only on the diclofenac treated side of 8 out of 20 participants |
| 3% diclofenac in 2.5% hyaluronic acid/5% imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT/2.5% hyaluronic acid + ALA‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
In summary, diclofenac was significantly more efficacious than its vehicle, 2.5% hyaluronic acid. It was also associated with more adverse events, based on the number of participants who withdrew because of adverse events and the number of participants who experienced skin irritation. Diclofenac treatment in 2.5% hyaluronic acid combined with ALA‐PDT might increase the long‐term efficacy compared to ALA‐PDT with 2.5% hyaluronic acid.
5‐fluorouracil (5‐FU)
Table 2 is an overview for 5‐fluorouracil.
| 5‐fluorouracil (5‐FU) compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk With comparator | Corresponding risk With intervention | |||||
| Participant complete clearance | ||||||
| 0.5% 5‐FU/Vehicle | Study population | RR 8.86 | 522 | ⊕⊕⊕⊕ | Data from 1, 2, and 4 week treatments were pooled together (Analysis 9.1) | |
| 15 per 1000 | 136 per 1000 | |||||
| Moderate | ||||||
| 0 per 1000 | 0 per 1000 | |||||
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | 71 per 1000 | 291 per 1000 | RR 4.08 | 142 | ⊕⊕⊝⊝ | 1 cycle (Analysis 62.1) |
| 0.5% 5‐FU/ALA‐PDT | 292 per 1000 | 499 per 1000 | RR 1.71 | 48 | ⊕⊝⊝⊝ | Data from blue light and pulsed dye laser were pooled |
| 0.5% 5‐FU/5.0% 5‐FU | See comment | See comment | Not estimable | 21 | ⊕⊝⊝⊝ | Intraindividual study: 0.5% and 5.0% 5‐FU = 9/21 |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU /10% masoprocol | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/5% Imiquimod | Study population | RR 1.85 | 89 | ⊕⊝⊝⊝ | ||
| 600 per 1000 | 1000 per 1000 | |||||
| Moderate | ||||||
| 555 per 1000 | 1000 per 1000 | |||||
| 5% 5‐FU/Carbon dioxide laser resurfacing | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Er:YAG laser resurfacing | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Cryotherapy | 680 per 1000 | 959 per 1000 | RR 1.41 | 49 | ⊕⊕⊝⊝ | Only data after the treatment |
| 5% 5‐FU/Trichloroacetic acid peel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean reduction in lesion counts | ||||||
| 0.5% 5‐FU/Vehicle | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | Data from 1, 2, and 4 week treatment were pooled. (Analysis 9.2) Results from another study (N = 177) with no SD: placebo: 2.7 lesions, 5‐FU = 8.8 lesions, GRADE = moderate |
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | 142 | ⊕⊕⊕⊝ | 1 cycle (Analysis 62.2) | |
| 0.5% 5‐FU/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5% 5‐FU/5.0% 5‐FU | See comment | See comment | Not estimable | 21 | ⊕⊕⊝⊝ | Intraindividual study: results with no SD: 0.5% 5‐FU = 8.8 lesions, 5.0% 5‐FU = 6.1 lesions |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | ‐ | 19 | ⊕⊕⊝⊝ | |
| 5% 5‐FU /10% masoprocol | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | ‐ | 49 | ⊕⊕⊝⊝ | |
| 5% 5‐FU/5% Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Carbon dioxide laser resurfacing | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Er:YAG laser resurfacing | See comment | See comment | Not estimable | 55 | ⊕⊕⊝⊝ | Results with no SD: number of lesions at 3 months:5‐FU = 13.2, resurfacing = 13.8, at 6 months:5‐FU = 12.5, resurfacing = 13.9, at 12 months: 5‐FU = 12.4, resurfacing = 14.2 |
| 5% 5‐FU/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Trichloroacetic acid peel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean percentage of reduction in lesion counts | ||||||
| 0.5% 5‐FU/Vehicle | The mean percentage of reduction in lesion counts ranged across control groups from | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | Data from 1 week treatment.(Analysis 9.3) Results from two other studies with no SD 1) (N = 207) placebo = 21.6%, 5‐FU = 69.5%, GRADE = low, 2)(N = 177) placebo = 34.4%, 5‐FU = 78.5%, GRADE = moderate |
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | |
| 0.5% 5‐FU/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5% 5‐FU/5.0% 5‐FU | See comment | See comment | Not estimable | 21 | ⊕⊕⊝⊝ | Intraindividual study: results with no SD: 0.5% 5‐FU = 67% and 5.0% 5‐FU = 47% |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU /10% masoprocol | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 49 | ⊕⊕⊕⊝ | |
| 5% 5‐FU/5% Imiquimod | See comment | See comment | Not estimable | 39 | ⊕⊕⊝⊝ | Results with no SD: 5% 5‐FU = 94%, 5% imiquimod = 66% |
| 5% 5‐FU/Carbon dioxide laser resurfacing | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 14 | ⊕⊝⊝⊝ | |
| 5% 5‐FU/Er:YAG laser resurfacing | See comment | See comment | Not estimable | 55 | ⊕⊕⊝⊝ | Results with no SD: at 6 months: 5‐FU = 79.2%, resurfacing 94.5%, at 12 months: 5‐FU = 76.6%, resurfacing = 91.1% |
| 5% 5‐FU/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Trichloroacetic acid peel | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 18 | ⊕⊝⊝⊝ | |
| Withdrawal due to adverse events | ||||||
| 0.5% 5‐FU/Vehicle | 0 per 1000 | N/A (5/119 = 42/1000) | RR 5.41 | 177 | ⊕⊝⊝⊝ | Data from 1, 2, and 4 week treatments were pooled.(Analysis 9.4) Another study reported 24/207 participants withdrew because of adverse events and 12 of them were in 4 week 5‐FU group. GRADE = low |
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | See comment | See comment | Not estimable | 142 | ⊕⊕⊝⊝ | There were no participant withdrawals in the first part of this three part study (incomplete data were given for the whole study). |
| 0.5% 5‐FU/ALA‐PDT | 0 per 1000 | N/A (1/12 = 83/1000) | RR 5.77 | 36 | ⊕⊕⊝⊝ | Data from blue light and pulsed dye laser were pooled |
| 0.5% 5‐FU/5.0% 5‐FU | See comment | See comment | Not estimable | 21 | ⊕⊕⊝⊝ | Intraindividual study: 16/21 discontinued treatment but did not withdraw: 4 because of 0.5%, 8 because of 5.0% , 4 because of both creams. |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | See comment | See comment | Not estimable | 19 | ⊕⊕⊝⊝ | Intraindividual study: 1 participant withdrew because of irritation but associated treatment was not specified. |
| 5% 5‐FU /10% masoprocol | 0 per 1000 | N/A (1/30 = 33/1000) | RR 2.71 | 57 | ⊕⊕⊝⊝ | |
| 5% 5‐FU/5% Imiquimod | 0 per 1000 | 0 per 1000 | Not estimable | 89 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| 5% 5‐FU/Carbon dioxide laser resurfacing | 250 per 1000 | 45 per 1000 | RR 0.18 | 17 | ⊕⊕⊝⊝ | |
| 5% 5‐FU/Er:YAG laser resurfacing | 0 per 1000 | N/A (1/27 = 37/1000) | RR 3.11 | 55 | ⊕⊕⊝⊝ | |
| 5% 5‐FU/Cryotherapy | 0 per 1000 | 0 per 1000 | Not estimable | 49 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 5% 5‐FU/Trichloroacetic acid peel | 0 per 1000 | 0 per 1000 | Not estimable | 18 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| Skin irritation | ||||||
| 0.5% 5‐FU/Vehicle | 654 per 1000 | 948 per 1000 | RR 1.45 | 384 | ⊕⊕⊕⊝ | Data from 1, 2, and 4 week treatments were pooled |
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5% 5‐FU/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5% 5‐FU/5.0% 5‐FU | 1000 per 1000 | 1000 per 1000 | ‐ | 21 | ⊕⊕⊕⊝ | Intraindividual study: All participants reported facial irritation in association with both creams |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | See comment | See comment | Not estimable | 19 | ⊕⊕⊕⊝ | Intraindividual study: 12 had more irritation with tretinoin, 4 had more with placebo, and 3 had equal irritation. |
| 5% 5‐FU /10% masoprocol | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/5% Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Carbon dioxide laser resurfacing | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Er:YAG laser resurfacing | 429 per 1000 | 703 per 1000 | RR 1.64 | 55 | ⊕⊕⊝⊝ | At the end of treatment |
| 5% 5‐FU/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Trichloroacetic acid peel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
In summary, 0.5% and 5% 5‐fluorouracil treatments resulted in similar efficacy and safety based on 1 study comparing them directly. 5‐Fluorouracil was significantly more efficacious than vehicle and cryotherapy, but similar to ALA‐PDT (see PDT overview table: Table 3) and carbon dioxide laser resurfacing. More studies are needed to confirm its superiority to masoprocol and imiquimod and its long‐term inferiority to Er:YAG laser resurfacing. In 1 study, additional treatment with 5‐fluorouracil increased the efficacy of cryotherapy with vehicle, but the efficacy (illustrative comparative risks) of cryotherapy alone in this study seemed much lower than other studies investigating cryotherapy (see cryotherapy overview table: Table 4). On the other hand, additional treatment with tretinoin did not improve the efficacy of 5‐fluorouracil. In general, 5‐fluorouracil treatment did not lead to withdrawal because of adverse events; however, substantial skin irritation was associated with this intervention.
| Photodynamic therapy compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk With comparator | Corresponding risk With intervention | |||||
| Participant complete clearance | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | 83 per 1000 | 500 per 1000 | RR 6 | 24 | ⊕⊝⊝⊝ | |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | 500 per 1000 | 500 per 1000 (225 to 1000) | RR 1 | 24 | ⊕⊝⊝⊝ | |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | 97 per 1000 | 602 per 1000 | RR 6.22 | 243 | ⊕⊝⊝⊝ | 1 treatment. (Analysis 47.1) Additional intraindividual study: ALA‐PDT: 16/35, placebo‐PDT = 2/35. GRADE = moderate |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | 500 per 1000 | 85 per 1000 | RR 0.17 | 24 | ⊕⊝⊝⊝ | |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | 474 per 1000 | 237 per 1000 | RR 0.5 | 72 | ⊕⊕⊝⊝ | Data from assessment at 8 weeks after the end of treatment (Analysis 49.2) |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | 471 per 1000 | 235 per 1000 | RR 0.5 | 68 | ⊕⊝⊝⊝ | Data from assessment at 8 weeks after the end of treatment |
| 0.5h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | 735 per 1000 | 235 per 1000 | RR 0.32 | 68 | ⊕⊕⊝⊝ | Data from assessment at 8 weeks after the end of treatment |
| 1h ALA‐red light PDT /2h ALA‐red light PDT (individual lesions) | 471 per 1000 | 475 per 1000 | RR 1.01 | 72 | ⊕⊝⊝⊝ | Data from assessment at 8 weeks after the end of treatment |
| 1h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | 735 per 1000 | 471 per 1000 | RR 0.64 | 72 | ⊕⊕⊝⊝ | Data from assessment at 8 weeks after the end of treatment |
| 2h ALA‐red light PDT/4h ALA‐red light PDT (individual lesions) | 735 per 1000 | 471 per 1000 | RR 0.64 | 68 | ⊕⊕⊝⊝ | Data from assessment at 8 weeks after the end of treatment (Analysis 49.2) |
| 3‐4h ALA‐red light PDT/3 to 4h placebo‐red light PDT (individual lesions) | 89 per 1000 | 527 per 1000 | RR 5.94 | 422 | ⊕⊕⊕⊕ | 1 treatment (Analysis 47.1) |
| 3% diclofenac in 2.5% hyaluronan gel + 4h ALA‐red light PDT /2.5% hyaluronan gel + 4h ALA‐red light PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 4h ALA‐red light PDT/Cryotherapy (individual lesions) | 443 per 1000 | 580 per 1000 | RR 1.31 | 297 | ⊕⊕⊝⊝ | |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Intraindividual study: ALA‐PDT + 5% imiquimod = 2/25; ALA‐PDT + placebo = 2/25 |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 16 | ⊕⊕⊕⊝ | Intraindividual study: ALA‐PDT = 6/16, MAL‐PDT = 7/16 |
| MAL‐PDT | ||||||
| All day 16% MAL‐daylight PDT /All day 8% MAL‐daylight PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2h MAL‐daylight PDT /3h MAL‐daylight PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2.5‐4h MAL‐red light PDT /2.5‐4h placebo‐red light PDT (individual lesions) | 147 per 1000 | 656 per 1000 | RR 4.46 | 482 | ⊕⊕⊕⊝ | |
| 3h MAL‐red light LED PDT /3h MAL‐broad visible + water‐filtered infrared A PDT (individual lesions) | 500 per 1000 | 575 per 1000 | RR 1.15 | 80 | ⊕⊕⊝⊝ | Data from assessment at 12 weeks after the end of treatment.(Analysis 53.1) |
| 3h MAL‐red light LED PDT /3h MAL‐daylight PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Single 3h MAL‐red light PDT /Multiple 3h MAL‐red light PDT [2 treatments 1 week apart] (individual lesions) | 755 per 1000 | 883 per 1000 | RR 1.17 | 211 | ⊕⊕⊝⊝ | |
| 3h MAL‐red light PDT /Cryotherapy (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean reduction in lesion counts | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT /2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3‐4h ALA‐red light PDT /3‐4h placebo‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid gel + 4h ALA‐red light PDT /2.5% hyaluronic acid gel + 4h ALA‐red light PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 10 | ⊕⊕⊝⊝ | Intraindividual study: at 6 weeks; diclofenac/hyaluronic acid (HA) + ALA‐PDT = 10.13, HA + ALA‐PDT= 9.9, at 6 months:; diclofenac/HA + ALA‐PDT = 11.56, HA + ALA‐PDT = 10.56, at 12 months; diclofenac/HA + ALA‐PDT = 12.5, HA + ALA‐PDT = 8.8 |
| 4h ALA‐red light PDT /Cryotherapy (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Results from intraindividual study without SD: ALA‐PDT + 5% imiquimod = 19.9 lesions; ALA‐PDT + placebo = 16.0 lesions |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 0.6 higher | ‐ | 15 | ⊕⊕⊝⊝ | |
| MAL‐PDT | ||||||
| All day 16% MAL‐daylight PDT /All day 8% MAL‐daylight PDT (field‐directedtreatments) | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 0.3 higher | ‐ | 29 | ⊕⊕⊝⊝ | |
| 2h MAL‐daylight PDT /3h MAL‐daylight PDT (field‐directedtreatments) | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 0.1 higher | 120 | ⊕⊕⊝⊝ | ||
| 2.5‐4h MAL‐red light PDT /2.5‐4h placebo‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light LED PDT /3h MAL‐broad visible + water‐filtered infrared A PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light LED PDT /3h MAL‐daylight PDT (field‐directedtreatments) | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 0.4 lower | ‐ | 29 | ⊕⊕⊝⊝ | |
| Single 3h MAL‐red light PDT /Multiple 3h MAL‐red light PDT [2 treatments 1 week apart] (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light PDT /Cryotherapy (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean percentage of reduction in lesion count | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT /2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3‐4h ALA‐red light PDT /3‐4h placebo‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid gel + 4h ALA‐red light PDT /2.5% hyaluronic acid gel + 4h ALA‐red light PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 4h ALA‐red light PDT /Cryotherapy (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Results from intraindividual study without SD: ALA‐PDT + 5% imiquimod = 86.7%; ALA‐PDT + placebo = 73.1% |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | ‐ | See comment | ‐ | ‐ | ‐ | Not reported |
| MAL‐PDT | ||||||
| All day 16% MAL‐daylight PDT /All day 8% MAL‐daylight PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 29 | ⊕⊕⊝⊝ | Data with no SD: 16% MAL‐daylight PDT = 76.9%, 8% MAL‐daylight PDT = 79.5%. |
| 2h MAL‐daylight PDT /3h MAL‐daylight PDT (field‐directedtreatments) | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was 2.6 higher | ‐ | 120 | ⊕⊕⊝⊝ | |
| 2.5‐4h MAL‐red light PDT /2.5‐4h placebo‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light LED PDT /3h MAL‐broad visible + water‐filtered infrared A PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light LED PDT /3h MAL‐daylight PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 29 | ⊕⊕⊝⊝ | Data with no SD: MAL‐red light LED PDT = 71%, MAL‐daylight PDT = 79%. |
| Single 3h MAL‐red light PDT /Multiple 3h MAL‐red light PDT [2 treatments 1 week apart] (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light PDT /Cryotherapy (individual lesions) | See comment | See comment | Not estimable | 240 | ⊕⊝⊝⊝ | Intraindividual studies with no SD: at 12 weeks: MAL‐PDT = 84.4%, cryotherapy = 74.5%, at 24 weeks: MAL‐PDT = 75‐86.7%, cryotherapy = 83.9‐87% |
| Withdrawal due to adverse events | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 24 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | 83 per 1000 | 28 per 1000 | RR 0.33 | 24 | ⊕⊕⊝⊝ | |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | 0 per 1000 | 0 per 1000 | Not estimable | 271 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | 83 per 1000 | 28 per 1000 | RR 0.33 | 24 | ⊕⊕⊝⊝ | |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 72 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 68 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 0.5h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 68 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 1h ALA‐red light PDT /2h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 72 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 1h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 72 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 2h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 68 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 3‐4h ALA‐red light PDT /3‐4h placebo‐red light PDT (individual lesions) | 0 per 1000 | 0 per 1000 | Not estimable | 391 | ⊕⊕⊕⊕ | There were no participant withdrawals due to adverse events. |
| 3% diclofenac in 2.5% hyaluronic acid gel + 4h ALA‐red light PDT /2.5% hyaluronic acid gel + 4h ALA‐red light PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 10 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 4h ALA‐red light PDT /Cryotherapy (individual lesions) | 0 per 1000 | 0 per 1000 | Not estimable | 255 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | 0 per 1000 | 0 per 1000 | Not estimable | 30 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 25 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 15 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| MAL‐PDT | ||||||
| All day 16% MAL‐daylight PDT /All day 8% MAL‐daylight PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 29 | ⊕⊕⊕⊝ | One of 30 participants withdrew because of adverse events unrelated to treatments. |
| 2h MAL‐daylight PDT /3h MAL‐daylight PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 120 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 2.5‐4h MAL‐red light PDT /2.5‐4h placebo‐red light PDT (individual lesions) | 0 per 1000 | N/A (3/130 = 23/1000) | RR 2 | 191 | ⊕⊝⊝⊝ | Two additional studies with no participant withdrawals because of adverse events (N = 211). GRADE = low |
| 3h MAL‐red light LED PDT /3h MAL‐broad visible + water‐filtered infrared A PDT (individual lesions) | 0 per 1000 | 0 per 1000 | Not estimable | 78 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 3h MAL‐red light LED PDT /3h MAL‐daylight PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 29 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Single 3h MAL‐red light PDT /Multiple 3h MAL‐red light PDT [2 treatments 1 week apart] (individual lesions) | 9 per 1000 | 3 per 1000 | RR 0.34 | 211 | ⊕⊕⊝⊝ | |
| 3h MAL‐red light PDT /Cryotherapy (individual lesions) | 11 per 1000 | 10 per 1000 | RR 0.94 | 379 | ⊕⊕⊕⊝ | Two additional intraindividual studies: 4 of 119 and 2 of 121 participants withdrew because of adverse events and one of them was related to MAL‐PDT. GRADE = low |
| Skin irritation | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT/4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2h ALA‐red light PDT/4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3 to 4h ALA‐red light PDT /3 to 4h placebo‐red light PDT (individual lesions) | 0 per 1000 | N/A (77/217 = 355/1000) | RR 59.72 | 300 | ⊕⊕⊕⊝ | Data for ALA‐PDT was given separately for two studies but not for placebo. Data from assessment after treatment (Analysis 47.7) |
| 3% diclofenac in 2.5% hyaluronic acid gel + 4h ALA‐red light PDT /2.5% hyaluronic acid gel + 4h ALA‐red light PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 4h ALA‐red light PDT /Cryotherapy (individual lesions) | 101 per 1000 | 371 per 1000 | RR 3.69 | 297 | ⊕⊕⊝⊝ | Assessment one day after the treatment (Analysis 51.2) |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| MAL‐PDT | ||||||
| All comparisons | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/ Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| ‐ | With comparator | With intervention | ‐ | ‐ | ‐ | ‐ |
| Participant complete clearance | ||||||
| Cryotherapy /Betulin‐based oleogel | 643 per 1000 | 784 per 1000 | RR 1.22 | 28 | ⊕⊝⊝⊝ | |
| Cryotherapy/cryotherapy with betulin‐based oleogel | 714 per 1000 | 786 per 1000 | RR 1.1 | 28 | ⊕⊝⊝⊝ | |
| Cryotherapy/5% 5‐FU | 958 per 1000 | 680 per 1000 | RR 0.71 | 49 | ⊕⊕⊝⊝ | Assessment after treatment (Analysis 43.1) |
| Vehicle with cryotherapy/0.5% 5‐FU with cryotherapy | 292 per 1000 | 70 per 1000 | RR 0.24 | 142 | ⊕⊕⊝⊝ | 1 cycle (Analysis 63.1) |
| Cryotherapy /Imiquimod | 846 per 1000 | 677 per 1000 | RR 0.8 | 51 | ⊕⊝⊝⊝ | 5% imiquimod (Analysis 44.1) |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | Study population | RR 0.2 | 311 | ⊕⊕⊕⊕ | Pooled data (5% and 3.75% imiquimod)(Analysis 64.1) Results from an additional intraindividual study: cryotherapy + vehicle = 5/27, cryotherapy+imiquimod = 8/27 GRADE = moderate | |
| 287 per 1000 | 57 per 1000 | |||||
| Moderate | ||||||
| 264 per 1000 | 53 per 1000 | |||||
| Cryotherapy /ALA‐red light PDT | 581 per 1000 | 442 per 1000 | RR 0.76 | 297 | ⊕⊕⊝⊝ | |
| Cryotherapy/MAL‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean reduction in lesion counts | ||||||
| Cryotherapy /Betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/cryotherapy with betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Vehicle + cryotherapy/0.5% 5‐FU + cryotherapy | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | 1 cycle (Analysis 63.2) |
| Cryotherapy /Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy /ALA‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/MAL‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean percentage of reduction in lesion counts | ||||||
| Cryotherapy /Betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/cryotherapy with betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Vehicle with cryotherapy/0.5% 5‐FU with cryotherapy | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | |
| Cryotherapy /Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | See comment | See comment | ‐ | 301 | ⊕⊝⊝⊝ | High heterogeneity (I2=86%) between 3.75% (parallel group, MD ‐34.10, 95% CI ‐41.38 to ‐26.82)) and 5.0% (intraindividual, MD ‐11.20, 95% CI ‐26.53 to 4.13) imiquimod studies. (Analysis 64.4) |
| Cryotherapy /ALA‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/MAL‐red light PDT | See comment | See comment | Not estimable | 240 | ⊕⊝⊝⊝ | Intraindividual studies with no SD: at 12 weeks: cryotherapy = 74.5%, MAL‐PDT= 84.4%, at 24 weeks: cryotherapy = 83.9‐87%, MAL‐PDT = 75‐86.7% |
| Withdrawal due to adverse events | ||||||
| Cryotherapy /Betulin‐based oleogel | 0 per 1000 | 0 per 1000 | Not estimable | 28 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy/cryotherapy with betulin‐based oleogel | 0 per 1000 | 0 per 1000 | Not estimable | 28 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy/5% 5‐FU | 0 per 1000 | 0 per 1000 | Not estimable | 49 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Vehicle with cryotherapy/0.5% 5‐FU with cryotherapy | See comment | See comment | Not estimable | 142 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events in the first part of this three part study (incomplete data were given for the whole study). |
| Cryotherapy /Imiquimod | 0 per 1000 | 0 per 1000 | Not estimable | 51 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | Study population | RR 0.93 | 312 | ⊕⊕⊕⊝ | Pooled data (5% and 3.75% imiquimod) (Analysis 64.6) | |
| 33 per 1000 | 30 per 1000 | |||||
| Moderate | ||||||
| 21 per 1000 | 20 per 1000 | |||||
| Cryotherapy /ALA‐ red light PDT | 0 per 1000 | 0 per 1000 | Not estimable | 297 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy/MAL‐ red light PDT | 11 per 1000 | 11 per 1000 | RR 1.06 | 379 | ⊕⊕⊕⊝ | Two additional intraindividual studies: 4 of 119 and 2 of 121 participants withdrew because of adverse events and one of them was related to MAL‐PDT. GRADE = low |
| Skin irritation | ||||||
| Cryotherapy /Betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/cryotherapy with betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Vehicle with cryotherapy/0.5% 5‐FU with cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy /Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | Study population | RR 0.39 | 311 | ⊕⊕⊕⊝ | Pooled data (5% and 3.75% imiquimod) | |
| 83 per 1000 | 32 per 1000 | |||||
| Moderate | ||||||
| 125 per 1000 | 49 per 1000 | |||||
| Cryotherapy /ALA‐red light PDT | 372 per 1000 | 100 per 1000 | RR 0.27 | 297 | ⊕⊕⊝⊝ | Assessment one day after the treatment (Analysis 46.2) |
| Cryotherapy/MAL‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
Imiquimod
Table 5 is an overview for imiquimod.
| Imiquimod compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| ‐ | With comparator | With intervention | ‐ | ‐ | ‐ | ‐ |
| Participant complete clearance | ||||||
| 2.5% imiquimod/placebo | 62 per 1000 | 277 per 1000 | RR 4.49 | 486 | ⊕⊕⊕⊕ | |
| 3.75% imiquimod/placebo | Study population | RR 6.45 | 730 | ⊕⊕⊕⊕ | ||
| 53 per 1000 | 343 per 1000 | |||||
| Moderate | ||||||
| 50 per 1000 | 322 per 1000 | |||||
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | 33 per 1000 | 301 per 1000 | RR 9.12 | 247 | ⊕⊕⊕⊝ | For all lesions |
| 5% imiquimod/placebo | Study population | RR 7.70 | 1871 | ⊕⊕⊕⊕ | ||
| 48 per 1000 | 371 per 1000 | |||||
| Moderate | ||||||
| 32 per 1000 | 246 per 1000 | |||||
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod /5% 5‐FU | See comment | See comment | ‐ | 89 | ⊕⊝⊝⊝ | The two studies was associated with high heterogeneity (I²= 93%) and the results could not be pooled together. One study favoured 5‐FU (RR 0.31, 95% CI 0.14 to 0.67] whereas the other did not (RR 0.88, 95% CI 0.73 to 1.06] (Analysis 22.1) |
| 5% imiquimod/Cryotherapy | 680 per 1000 | 843 per 1000 | RR 1.24 | 51 | ⊕⊝⊝⊝ | |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | 91 per 1000 | 225 per 1000 | RR 2.48 | 64 | ⊕⊕⊝⊝ | For all lesions.(Analysis 65.1) Results from an additional intraindividual study: cryotherapy + imiquimod side (8/27 = 30%), cryotherapy alone side (5/27 = 19%), GRADE = low |
| 5% imiquimod/ALA‐PDT | ‐ | Not reported | ||||
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Intraindividual study: ALA‐PDT + 5% imiquimod = 2/25; ALA‐PDT + placebo = 2/25 |
| Mean reduction in lesion counts | ||||||
| 2.5% imiquimod/placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3.75% imiquimod/placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/placebo | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 2.20 higher | ‐ | 12 | ⊕⊕⊝⊝ | Results from an additional intraindividual study with no SD (N = 21): 5% imiquimod: 3.9 lesions, placebo = 0.5 lesions, GRADE = very low |
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod /5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Results from intraindividual study without SD: ALA‐PDT + 5% imiquimod= 19.9 lesions; ALA‐PDT + placebo= 16.0 lesions |
| Mean percentage of reduction in lesion counts | ||||||
| 2.5% imiquimod/placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3.75% imiquimod/placebo | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was 46.90 higher | ‐ | 247 | ⊕⊕⊕⊝ | |
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was 34.1 higher | ‐ | 247 | ⊕⊕⊕⊝ | For all lesions (Analysis 65.2) |
| 5% imiquimod/placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod /5% 5‐FU | See comment | See comment | Not estimable | 39 | ⊕⊕⊝⊝ | Results with no SD: 5% imiquimod = 66%, 5% 5‐FU = 94% |
| 5% imiquimod/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was 11.2 higher | ‐ | 27 | ⊕⊕⊝⊝ | For all lesions.(Analysis 65.2) Results from an additional intraindividual study: cryotherapy‐5% imiquimod = 73.2+27.1%, cryotherapy + vehicle = 62.0+30.3%. GRADE = moderate |
| 5% imiquimod/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Results from intraindividual study without SD: ALA‐PDT + 5% imiquimod = 86.7% ; ALA‐PDT + placebo = 73.1 % |
| Withdrawal due to adverse events | ||||||
| 2.5% imiquimod/placebo | 19 per 1000 | 9 per 1000 | RR 0.5 | 486 | ⊕⊕⊕⊝ | |
| 3.75% imiquimod/placebo | 19 per 1000 | 17 per 1000 | RR 0.92 | 483 | ⊕⊕⊕⊝ | |
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | 32 per 1000 | 41 per 1000 | RR 1.3 | 247 | ⊕⊕⊝⊝ | |
| 5% imiquimod/placebo | Study population | RR 2.59 | 2290 | ⊕⊕⊕⊝ | (Analysis 20.5) Four small sample size studies with no participant withdrawal are not included in meta‐analysis: pooled data, imiquimod 0/79 and placebo 0/31. Additional two intraindividual studies: no participant withdrew because of adverse events (0/42) GRADE = very low (both studies had more than 20% participant lost). | |
| 21 per 1000 | 56 per 1000 | |||||
| Moderate | ||||||
| 5 per 1000 | 13 per 1000 | |||||
| High | ||||||
| 0 per 1000 | 0 per 1000 | |||||
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | 0 per 1000 | 0 per 1000 | Not estimable | 49 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 5% imiquimod /5% 5‐FU | 0 per 1000 | 0 per 1000 | Not estimable | 50 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 5% imiquimod/Cryotherapy | 0 per 1000 | 0 per 1000 | Not estimable | 51 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | 30 per 1000 | 10 per 1000 | RR 0.34 | 65 | ⊕⊕⊝⊝ | |
| 5% imiquimod/ALA‐PDT | 0 per 1000 | 0 per 1000 | Not estimable | 30 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | 0 per 1000 | 0 per 1000 | Not estimable | 25 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| Skin irritation | ||||||
| 2.5% imiquimod/placebo | 6 per 1000 | 21 per 1000 | RR 3.45 | 486 | ⊕⊕⊕⊝ | |
| 3.75% imiquimod/placebo | 6 per 1000 | 30 per 1000 | RR 4.86 | 484 | ⊕⊕⊕⊝ | |
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | 8 per 1000 | 56 per 1000 | RR 6.72 | 247 | ⊕⊕⊝⊝ | |
| 5% imiquimod/placebo | 5 per 1000 | 18 per 1000 | RR 3.68 | 708 | ⊕⊕⊕⊝ | Additional intraindividual study: similar mild irritation between the two treatment sides (N = 20) GRADE = very low |
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | 121 per 1000 | 194 per 1000 | RR 1.6 | 64 | ⊕⊕⊝⊝ | |
| 5% imiquimod/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
In summary, imiquimod was significantly more efficacious than vehicle, but similar to cryotherapy and 3% diclofenac in 2.5% hyaluronic acid (based on another efficacy outcome presented below). More studies are needed to confirm its inferiority to 5% 5‐fluorouracil. Additional treatment with 3.75%, but not 5%, imiquimod increased the efficacy of cryotherapy, but the efficacy (illustrative comparative risks) of cryotherapy with vehicle in this study seemed much lower than other studies investigating cryotherapy alone (see cryotherapy overview table: Table 4). More data are needed to be able to compare 5% imiquimod to photodynamic therapy, and additional treatment with imiquimod did not improve the efficacy of photodynamic therapy. Treatment with 5% imiquimod resulted in a larger number of participant withdrawals due to adverse events than treatment with 2.5% and 3.75% imiquimod.
Cryotherapy
Table 4 is an overview for cryotherapy.
In summary, cryotherapy had similar efficacy to betulin‐based oleogel and imiquimod. Cryotherapy was significantly inferior to 5‐fluorouracil and ALA‐PDT. No conclusion could be made on its efficacy compared to MAL‐PDT based on our primary outcomes. Additional treatment with 5‐fluorouracil or imiquimod might increase the efficacy of cryotherapy, but these studies had generally lower efficacy associated with cryotherapy with vehicle treatment than the other studies with cryotherapy alone. Cryotherapy was generally not associated with withdrawal due to adverse events and had less skin irritation than ALA‐PDT3.
Photodynamic therapy (PDT)
Table 3 is an overview for photodynamic therapy.
In summary, similar efficacy was obtained for the two photosensitising agents, ALA and MAL, under similar photodynamic therapy conditions. The use of ALA/MAL with blue or red light PDT resulted in similar results, which were significantly different than vehicle with blue or red light PDT. Longer incubation (4 hours [h]) with ALA resulted in better results compared to shorter incubation time (0.5, 1, and 2 hours). Consequently, 4‐hour incubation with ALA followed by PDT was significantly more efficacious than cryotherapy, but 1‐hour incubation with ALA followed by PDT (blue light or pulsed dye laser) was not significantly different than 0.5% 5‐fluorouracil. Additional treatment with 5% imiquimod did not improve the efficacy of ALA‐PDT. With MAL‐PDT, similar efficacy was observed for red light, broad visible light with water‐filtered infrared A, and daylight. With daylight PDT, no difference was found between 16% and 8% MAL or between 2‐hour and 3‐hour incubation with MAL before daylight exposure. Based on our primary outcomes, no conclusion could be made on MAL‐red light PDT efficacy compared to cryotherapy or the benefit of multiple versus single treatment. Photodynamic therapy generally did not lead to withdrawal because of adverse events. Based on the only two studies reporting skin irritation, incubation with ALA might cause skin irritation.
B) All interventions
This section is addressed as planned in 'Criteria for considering studies for this review' and 'Types of interventions':
(1) Prescription‐based topical treatments
(2) Prescription‐based oral drugs
(3) Mechanical interventions
(4) Chemical interventions
(5) Combinations of topical and oral treatments with mechanical or chemical interventions
(1) Prescription‐based topical treatments
Prescription‐based topical treatments, which are generally field‐directed treatments, were addressed in alphabetical order: adapalene gel, aretinoid methyl sulfone (Ro 14‐9706), betulin‐based oleogel, calcipotriol, colchicine, diclofenac, 2‐(Difluoromethyl)‐dl‐ornithine (DFMO), 5‐fluorouracil (5‐FU), β‐1,3‐D‐glucan, imiquimod, ingenol mebutate (PEP005), isotretinoin, masoprocol, nicotinamide, resiquimod, sunscreen, DL‐α‐tocopherol (vitamin E), and tretinoin.
Adapalene gel
This intervention was addressed by only 1 study (Kang 2003), which compared the efficacy of 0.1% adapalene gel, 0.3% adapalene gel, and vehicle gel for the treatment of actinic keratoses on the face, ears, scalp, arms, and back of the hands. Participants were treated with adapalene gel or placebo daily for four weeks, followed by twice‐daily applications for up to nine months. The assessment was performed at the end of treatment. There was no major source of possible bias.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 90 participants) | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 90 participants) |
| Investigator | ‐ | ‐ | Absolute values |
With regard to the outcome 'global Improvement Indices (investigator): completely improved or cleared', we detected no significant difference in efficacy between adapalene and placebo treatments (Analysis 1.1), or between 0.1% and 0.3% adapalene (Analysis 2.1). The proportion of participants who had positive outcomes (clear, marked, moderate, or slight improvements) was higher in participants treated with adapalene (52/60) than those treated with placebo (21/30), and the proportion of participants graded unchanged or worse was higher in those treated with placebo (9/30) than those that were adapalene‐treated (8/60) (Kang 2003).
Mean changes [reduction (‐) for adapalene and increase (+) for placebo] in the number of actinic keratoses from baseline were the means of measuring efficacy. Compared to placebo, both 0.1% and 0.3% adapalene gel resulted in a significant reduction in mean lesion counts [0.1% = MD ‐2.00, 95% CI ‐2.73 to ‐1.27, and 0.3% = MD ‐4.00, 95% CI ‐4.73 to ‐3.27; Analysis 1.2]. The 0.3% adapalene gel was significantly more efficient than 0.1% adapalene gel in reducing the number of lesions [MD ‐2.00, 95% CI ‐2.46 to ‐1.54; Analysis 2.2].
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 90 participants) | Skin irritation | Minor adverse events excluding skin irritation (N = 90 participants) | Cosmetic outcome (N = 42 participants) |
| x | ‐ | x | Graph |
Three participants in the 0.3% adapalene group had to withdraw because of these adverse events: skin irritation, dermatitis, and eye dryness. This number of participants was not significantly different from the placebo group (Analysis 1.3) or the 0.1% adapalene treated‐group (Analysis 2.3).
Dermatitis was the only minor adverse event reported quantitatively. Dermatitis was significantly more frequent in the participants treated with adapalene (20/60) than with placebo (3/30) [RR 3.33, 95% CI 1.08 to 10.34; Analysis 1.4], corresponding to a NNT for an additional harmful outcome of 4.3. In contrast, the number of participants experiencing dermatitis was similar in the 0.1% and 0.3% adapalene‐treated groups (Analysis 2.4).
Kang 2003 graphically reported improvements in the following clinical features of photoageing of the skin: mottled hyperpigmentation, fine wrinkles, coarse wrinkles, and rosy glow. The authors stated that a significant difference between adapalene and placebo was detected for global appearance, mottled hyperpigmentation, fine wrinkles, and rosy glow, but not for coarse wrinkles. The exact percentages of participants with improvement in mottled hyperpigmentation were given (55% in the 0.1% group, 65% in the 0.3%, and 25% in the placebo group), but only a subpopulation of participants were evaluated, and the number of participants for each treatment group was not given. Thus, no statistical analysis was performed on this data.
To summarise, adapalene gel was more efficient than placebo in treating actinic keratoses. In addition, 0.3% adapalene gel gave better results than 0.1% adapalene gel, based on the mean reduction in lesion counts without an increase in adverse events.
Aretinoid methyl sulfone (Ro 14‐9706)
Ro 14‐9706 versus 0.05% tretinoin
This intervention was addressed by only 1 intraindividual study (Misiewicz 1991), which compared the efficacy of 0.05% Ro 14‐9706 and 0.05% tretinoin applied twice‐daily for 16 weeks for the treatment of facial actinic keratoses. Assessment was performed at the end of the 16‐week treatment. There was no major source of possible bias.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 25 participants) | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 25 participants) |
| x | ‐ | ‐ | Percentages |
Because of the study design, i.e. intraindividual study, the data for 'global improvement indices' for participants receiving the two different interventions could not be included in a meta‐analysis, but is presented in the following table.
| Number of participants with the following improvements | Ro14‐9706 | Tretinoin |
| Complete response | 0/25 | 2/25 |
| Partial response | 12/25 | 10/25 |
| No response | 13/25 | 11/25 |
| Worsening | 0/25 | 2/25 |
Areas treated with tretinoin cream showed an initial increase in the number of lesions (weeks 3 to 9), which eventually decreased after week 10. Ro 14‐9706 showed no initial increase in number of actinic keratoses lesions, but a gradual decline over time. The resulting mean percentage of reduction in lesion counts was significantly higher in the group treated with Ro 14‐9706 than the group treated with tretinoin (MD 7.50, 95% CI 6.57 to 8.43; Analysis 3.1).
Secondary outcomes
Misiewicz 1991 reported none of our secondary outcomes.
To summarise, Ro 14‐9706 treatment showed better overall reduction in lesion counts, whereas tretinoin treatment, which showed an initial increase in lesions, resulted in more participants with complete response.
Betulin‐based oleogel
Studies using betulin‐based oleogel used this treatment as a comparator for cryotherapy. The results will be discussed in the cryotherapy section below.
Calcipotriol (vitamin D)
This intervention was addressed by only one study (Seckin 2009), which compared the efficacy of calcipotriol (vitamin D) to placebo treatment for actinic keratoses on the face and scalp. One treatment was applied on 1 randomised side of the face, and the other treatment on the other side twice daily for 12 weeks. Assessment was performed at the end of the 12‐week treatment. There was possible attrition and reporting bias associated with this study.
Primary outcomes
| Study | Global improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 8 participants) |
| ‐ | ‐ | ‐ | Absolute values, percentages |
Mean changes [reduction (‐) for calcipotriol and increase (+) for placebo] in the number of actinic keratoses from baseline were the means of measuring efficacy. In contrast to placebo, calcipotriol reduced the number of lesions; however, the overall effect was not statistically different (Analysis 4.1). In addition, no statistical difference in the mean percentage of reduction in lesion counts was detected by the authors (Seckin 2009).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 8 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (N = 8 participants) |
| x (none lost) | ‐ | ‐ | x |
There were no participant withdrawals due to adverse events.
The reduction of the total score for cosmetic appearance, which rated erythema, desquamation, and induration of a target lesion, was not different between the calcipotriol and placebo groups (Analysis 4.2).
To summarise, the data available for treatment of actinic keratoses with calcipotriol could not demonstrate its superiority for efficacy or cosmetic outcomes compared to placebo.
Colchicine
This intervention was addressed by only 1 study (Akar 2001), which compared the efficacy of 1% colchicine to 0.5% colchicine for actinic keratosis lesions. Both 0.5% and 1% colchicine were applied twice daily for 10 days on the face, scalp, and upper extremities. Assessment was performed at four weeks. There was no major source of possible bias.
Primary outcomes
| Study | Global improvement indices for completely improved or cleared | Participant complete clearance (N = 16 participants) | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 16 participants) |
| ‐ | x | ‐ | Absolute values |
In general, 0.5% and 1% colchicine treatments resulted in similar efficacy, with 7/8 and 6/8 participants completely cleared (Analysis 5.1) and similar mean reduction in lesion counts for all lesions (Analysis 5.2) or by anatomical locations (Analysis 5.3).
Secondary outcomes
| Study | Withdrawal due to adverse events | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (N = 16 participants) |
| ‐ | ‐ | ‐ | x |
The final cosmetic results in successful cases were good for both colchicine concentrations, as supported by the quantitative analysis of the number of participants with decreased infiltration and disappearance of crust at one month (Analysis 5.4), which showed no difference between the two treatments.
To summarise, 0.5% and 1% colchicine had similar efficacy and cosmetic outcomes and showed high efficacy (81% of participants completely cleared); however, these conclusions were based on a small sample size.
Diclofenac
Diclofenac versus vehicle
This intervention was addressed by 7 studies (Fariba 2006; Gebauer 2003; McEwan 1997; Rivers 2002; Solaraze study 2; Ulrich 2010; Wolf 2001) comparing 3% diclofenac in 2.5% hyaluronic acid gel to 2.5% hyaluronic acid gel, for the treatment of actinic keratoses. The characteristics of these studies are presented in the following table. There was possible attrition bias (McEwan 1997; Ulrich 2010), reporting bias (Solaraze study 2; Ulrich 2010), and other bias (Fariba 2006; McEwan 1997).
| Characteristic | |||||||
| Study design | Parallel‐group | Parallel‐group | Parallel‐group | Parallel‐group | Parallel‐group | Intraindividual | Parallel‐group |
| Anatomical locations | Face, scalp, ear, neck, lower arm/elbow, hand, lower leg/knee | Forehead, central face, scalp, arms, hands | Forehead, central face, scalp, dorsum of hands | Face, scalp, forehead, arm, forearm, back of hands | Head/neck, hands, or arms | Face or scalp | Face, scalp, hands |
| Diclofenac concentration (%) | 3 | 3 | 3 | 3 | 3 | 3 | 3 |
| Frequency of treatment | Twice daily | Twice daily | Twice daily | Twice daily | Twice daily | Twice daily | Twice daily |
| Duration given (days) | 56 to 168 | 90 | 30, 60 | 90 | 90 | 90 | 112 |
| Assessment | At the end of 24‐week treatment | 4 weeks after the end of treatment | 4 weeks after the end of treatment | 4 weeks after the end of treatment | At the end of 12‐week treatment and 4 weeks after the end of treatment | At the end of 12‐week treatment | At the end of 16‐week treatment |
In Ulrich 2010, participants were immunosuppressed (organ transplant patients). Three of the included studies (Rivers 2002; Solaraze study 2; Wolf 2001) were part of the Solaraze product insert, and the number of participants experiencing at least one adverse event was pooled and reported in the Solaraze study 2.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 312 participants) | Participant complete clearance (N = 490 participants) | Participant partial (> 75%) clearance (N = 28 participants) | Mean reduction (changes) in lesion counts (N = 345 participants) |
| ‐ | x | ‐ | ‐ | |
| Investigator and participant | x | ‐ | ‐ | |
| Investigator and participant | x | ‐ | Absolute values | |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | ‐ | Absolute values | |
| ‐ | ‐ | ‐ | ‐ | |
| ‐ | x | x | Percentages |
Efficacy measurements using investigator and participant global improvement indices for the outcome 'completely improved' showed the superiority of the 3% diclofenac in 2.5% hyaluronic acid gel over 2.5% hyaluronic acid gel alone for 60‐day treatment [investigator: RR 3.06, 95% CI 1.21 and 7.77, NNT= 4.8; participant: RR 2.86, 95% CI 1.12 to 7.32, NNT = 5.3] and 90‐day treatment [investigator: RR 2.50, 95% CI 1.37 to 4.55, NNT = 3.6; participant: RR 2.44, 95% CI 1.28 to 4.64], but not for 30‐day treatment [investigator and participant: RR 4.00, 95% CI 0.89 to 17.89] (Analysis 6.1; Analysis 6.2).
We performed seven meta‐analyses for the outcome 'participant complete clearance'.
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Analysis for efficacy assessment at the end of treatment: The 2 studies that reported the efficacy assessment at the end of treatment used a treatment period longer than 30 days and showed the superiority of the diclofenac treatment over 2.5% hyaluronic acid gel alone [RR 1.95, 95% CI 1.21 to 3.13, NNT = 7.1] (Analysis 6.3).
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Analysis for efficacy assessment after a 30‐day follow‐up for target lesions, i.e. present at baseline: This was similar to the global improvement indices for completely improved 60‐ and 90‐day treatments, but not 30‐day treatment. Diclofenac/hyaluronic acid showed superiority over the vehicle for target lesions [(60 days: RR 3.27, 95% CI 1.30 to 8.21, NNT = 4.3) (90 days: RR 2.87, 95% CI 1.84 to 4.48, NNT = 3.4) (Analysis 6.4)].
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Analysis for efficacy assessment after a 30‐day follow‐up for all lesions, i.e. target and new lesions: Again, participant complete clearance was significantly different for 60‐day therapy (RR 3.83, 95% CI 1.37 to 10.71, NNT = 4.3) and 90‐day therapy (RR 2.20, 95% CI 1.40 to 3.44, NNT = 4.5), but not after 30 days of therapy (RR 3.50, 95% CI 0.76 to 16.01). The pooled RR was 2.46 (95% CI 1.66 to 3.66, NNT = 5.4) (Analysis 6.5). The small sample sizes resulted in no significant difference in the RRs for participant complete clearance between the different anatomical locations.
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Analysis for 30‐day treatment with subgroups by anatomical locations (Analysis 6.6).
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Analysis for 60‐day treatment with subgroups by anatomical locations (Analysis 6.7).
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Analysis for 90‐day treatment with subgroups by anatomical locations: In contrast to locations on the face or forehead, the RRs for scalp, arm/forearms, and back of the hands did not favour diclofenac for 90‐day treatment over vehicle, because of the variability between studies (Analysis 6.8).
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Analysis of immunosuppressed participants with efficacy assessment after a 30‐day follow‐up (Analysis 6.9): In immunosuppressed participants, statistically significant superiority of 16‐week treatment with diclofenac over placebo could not be demonstrated despite a large effect for participant complete clearance (RR 5.78, 95% CI 0.38 to 87.35; Analysis 6.9) or partial (> 75%) clearance (RR 3.55, 95% CI 0.57 to 21.94; Analysis 6.10). This was probably due to the small number of participants involved in this single study. Further studies are needed to be able to conclude on the efficacy of diclofenac in immunosuppressed participants.
The healing properties of diclofenac seem to continue after treatment. There was no significant difference in the mean reduction of lesion counts at the end of 60‐ to 90‐day treatment between diclofenac and vehicle (2.5% hyaluronic acid gel) (Analysis 6.11). In contrast, a significantly better reduction in lesion counts was achieved by the diclofenac treatment compared to 2.5% hyaluronic acid gel alone after a 30‐day follow‐up (MD of at least 2.00; Analysis 6.12). For the immunosuppressed participants, a mean reduction of 53% in the lesion counts was observed for diclofenac, whereas a mean increase of 17% was observed for 2.5% hyaluronic acid gel alone. A statistical analysis could not be performed because standard deviations were not provided.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 644 participants) | Skin irritation (N = 20 participants) | Minor adverse events excluding skin irritation (N = 462 participants) | Cosmetic outcome (N = 32 participants) |
| x | ‐ | ‐ | ‐ | |
| x | ‐ | In general (excluding dermatology because it could include skin irritation) and specific adverse events based on body system | ‐ | |
| x | ‐ | x | ‐ | |
| ‐ | ‐ | ‐ | ‐ | |
| x | ‐ | x | ‐ | |
| x (intraindividual) | x | ‐ | ‐ | |
| x | ‐ | ‐ | x |
None of the participants (N = 20) in the intraindividual study by Fariba 2006 withdrew because of adverse events. In contrast, significantly more participants withdrew because of adverse events in the 3% diclofenac in 2.5% hyaluronic acid group compared to the 2.5% hyaluronic acid group for the other studies (RR 3.59, 95% CI 1.92 to 6.70; Analysis 6.13), corresponding to a NNT of 9.4 for an additional harmful outcome. In the immunosuppressed participants, 2 out of 24 participants in the diclofenac with 2.5% hyaluronic acid group withdrew because of adverse events, whereas none of the 8 participants receiving 2.5% hyaluronic acid alone withdrew.
Fariba 2006 reported irritation only on the side treated with diclofenac in 8 of 20 participants.
Minor adverse events were reported for several body systems, and only the number of participants experiencing minor adverse events related to metabolic and nutritional disorders was significantly higher for diclofenac/hyaluronic acid (RR 5.09, 95% CI 1.16 to 22.22; Analysis 6.28), corresponding to a NNT of 7.2 for an additional harmful outcome. Unfortunately, the authors of the study (Wolf 2001) did not give the details of the adverse events related to metabolic and nutritional disorders. A large number of specific minor adverse events have been reported by only one study, and none of them were significantly different between the two groups. One of the minor adverse events reported by the three studies was dry skin. Dry skin was significantly more frequent in the diclofenac/hyaluronic acid group (RR 2.40, 95% CI 1.20 to 4.78; Analysis 6.20), corresponding to a NNT of 4.4 for an additional harmful outcome. Two studies reported two adverse events related to the nervous system, hyperaesthesia and paraesthesia, which were localised to treatment sites by Rivers 2002. The number of participants experiencing both neurological adverse events were not different between the two treatment groups.
Ulrich 2010 mentioned that all immunosuppressed participants on the diclofenac treatment group had "cosmetically appealing results" four weeks after the end of the study, but did not mention anything about the hyaluronic acid (vehicle) group.
To summarise, diclofenac was in general significantly more effective than hyaluronic acid alone, but it was associated with significantly more withdrawals due to adverse events. Unfortunately, the data reported by the included studies did not allow comparison of efficacy and safety between immunosuppressed and immunocompetent participants.
Diclofenac versus imiquimod
This intervention was addressed by 1 open‐label study (Kose 2008), which compared the efficacy of 3% diclofenac in 2.5% hyaluronic acid (once daily for 12 weeks) and 5% imiquimod (3 times per week for 12 weeks) for the treatment of actinic keratoses on the face and scalp. Assessment was performed at the end of the 12‐week treatment. There was possible performance, detection, and reporting bias in this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 49 participants) | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts |
| Investigators and participants | ‐ | ‐ | ‐ |
No significant difference was found between diclofenac or imiquimod either by the investigator global improvement indices (Analysis 7.1) or by the participant global improvement indices (Analysis 7.2).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 49 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | ‐ | ‐ | ‐ |
There were no participant withdrawals due to adverse events.
To summarise, diclofenac and imiquimod treatments were equivalent.
Other comparisons
The efficacy of diclofenac in combination with photodynamic therapy will be discussed in the phototherapy section.
2‐(Difluoromethyl)‐dl‐ornithine (DFMO)
This intervention was addressed by 1 intraindividual study (Alberts 2000), which compared the efficacy of 10% 2‐(Difluoromethyl)‐dl‐ornithine (DFMO) with placebo for the treatment of actinic keratosis. The creams were applied to the randomised forearms twice daily for six months. Assessment was performed at the end of the 24‐week treatment. There was possible reporting bias in this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 42 participants) |
| ‐ | ‐ | ‐ | Absolute values and percentages |
The mean numbers of lesions at baseline were high [DFMO‐treated arms: 28.1 + 17.1 (SD); placebo‐treated arms: 29.2 + 18.7], and the reduction rates of lesion counts were relatively low: 23.5% for DFMO and 2.4% for placebo. Moreover, because of the large variability associated with this efficacy outcome, the mean difference (MD) of the absolute mean reduction in lesion counts did not reach statistical significance (MD 5.90, 95% CI ‐3.84 to 15.64; Analysis 8.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 42 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | ‐ | ‐ | ‐ |
Two participants for this intraindividual study withdrew because of adverse events.
To summarise, with severe actinic keratosis, DFMO had limited efficacy and is associated with severe inflammatory reactions.
5‐Fluorouracil (5‐FU)
5‐Fluorouracil versus placebo
This intervention was addressed by 3 studies (Jorizzo 2002;Jorizzo 2004; Weiss 2002). Jorizzo 2002 and Weiss 2002 compared 0.5% 5‐fluorouracil to vehicle cream applied daily for 1, 2, or 4 weeks on lesions located on the face or frontal scalp, and the data were part of the Carac product insert. Jorizzo 2004 reported results from an assessment 4 weeks after 1 week of treatment with either 0.5% 5‐fluorouracil or vehicle cream prior to cryotherapy treatment on lesions on the face, scalp, ears, neck, and lips. Assessment was performed at four weeks after the end of treatment. There was possible performance, detection, attrition, and reporting bias associated with Jorizzo 2002 and Weiss 2002 studies. The latter also has other possible sources of bias.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 351 participants) | Participant complete clearance (N = 528 participants) | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 528 participants) |
| Scores (not included) | x | ‐ | Absolute values | |
| Scores (not included) | x | ‐ | Absolute values | |
| ‐ | x | ‐ | Absolute values |
The data for participant complete clearance from these studies was separated into subgroups based on duration of treatment. Subgroup analyses (Analysis 9.1) showed that treatment with 0.5% 5‐fluorouracil treatment resulted in a significantly higher number of completely cleared participants than the placebo cream when applied for 1 week (NNT = 15.4), 2 weeks (NNT = 7.1), and 4 weeks (NNT = 3.2), resulting in an overall significantly better efficacy for 5‐fluorouracil (RR 8.86, 95% CI 3.67 to 21.40, NNT = 8.5; Analysis 9.1). When participant complete clearance for the different treatment durations were compared, daily application of 0.5% 5‐fluorouracil for 4 weeks was found to have significantly higher efficacy than treatment for 1 week and 2 weeks (RR 0.39, 95% CI 0.19 to 0.81 and RR 0.56, 95% CI 0.36 to 0.87, respectively; Analysis 10.1). No difference was found between treatment for one week and treatment for two weeks. We must be cautious in our interpretation of these results because the design of the studies did not blind the participants and assessor for the treatment duration.
Mean reduction in lesion counts was presented as absolute values, percentages, or both. In Jorizzo 2002, only the percentages without the associated standard deviations were presented, as shown in the following table. Jorizzo 2004 presented both absolute values and percentages (table) with their associated standard deviation. Analysis of the absolute values showed a significant reduction in lesion counts with 1 week of 5‐fluorouracil compared to placebo (MD 5.40, 95% CI 2.94 to 7.86; Analysis 9.2). Finally, Weiss 2002 presented the absolute values (placebo: 2.7, 1 week: 8.8, 2 weeks: 11.7, and 4 weeks: 11.1) and percentages (table) without their associated standard deviations. In all studies, the mean percentages of reduction in lesion counts were higher in the 5‐fluorouracil‐treated groups than placebo.
| Mean percentage of reduction in lesion counts | Placebo | 5‐fluorouracil (1 week) | 5‐fluorouracil (2 weeks) | 5‐fluorouracl (4 weeks) | 5‐fluorouracl (pooled) |
| Jorizzo 2002 (N = 207 participants) | 21.6% | 69.5% | 86.1% | 91.7% | 82.4% |
| Jorizzo 2004 (N = 144 participants) | 28.8% + 32.6% (SD) | 62.4% + 32.6% (SD) | N/A | N/A | 62.4% |
| Weiss 2002 (N = 177 participants) | 34.4% | 78.5% | 83.6% | 88.7% | 83.6% |
N/A = not available
Based on the data from Jorizzo 2004, the mean percentage of reduction in lesion counts for 1 week of treatment with 0.5% 5‐fluorouracil compared to vehicle was statistically significant in favour of 5‐fluorouracil (MD 33.60, 95% CI 22.88 to 44.32; Analysis 9.3).
Secondary outcomes
Because the safety analysis in Jorizzo 2004 included cryotherapy treatment, this study was excluded from this section. All the safety outcomes, except 'skin irritation' in general, were pooled together in the Carac product insert and were reported as in the Jorizzo 2002 study.
| Study | Withdrawal due to adverse events (N = 384 participants) | Skin irritation (N = 384 participants) | Minor adverse events excluding skin irritation (N = 384 participants) | Cosmetic outcome |
| x | x | In general (excluding dermatology because it could include skin irritation) and specific adverse events based on body system | ‐ | |
| x | x | In general (excluding dermatology because it could include skin irritation) and specific adverse events based on body system | ‐ |
Analysis of data reported by Weiss 2002 showed that the number of participants who withdrew because of adverse events had a tendency to be higher in the 5‐fluorouracil‐treated group compared to the placebo‐treated group (Analysis 9.4). The number of withdrawals due to adverse events had a tendency to increase with longer treatment with 5‐fluorouracil (Analysis 10.2), but this was not statistically significant. Similar to Weiss 2002, Jorizzo 2002 had 4 treatments arms (1, 2, and 4 weeks of 5‐fluorouracil and placebo). In this study, a total of 24 participants out of 207 withdrew because of adverse events, but the authors only mentioned that 12 of them (50%) were in the 4‐week group (N = 45). Together, these data suggest that severe adverse events are indeed associated with 4‐week treatment with 5‐fluorouracil.
Similarly, the number of participants experiencing facial irritation was significantly higher in the 5‐fluorouracil‐treated group than in the group treated with placebo (RR 1.45, 95% CI 1.27 to 1.65, NNT = 3; Analysis 9.5) without any difference between treatment durations (Analysis 10.3). The number of participants experiencing skin irritation was slightly lower in the 1‐week group than the 2 other 5‐fluorouracil groups, i.e. 2 and 4 weeks of treatments. Irritation related to treatment was mostly of mild to moderate severity.
None of the analyses for our outcome 'minor adverse events' resulted in significant differences between 5‐fluorouracil and vehicle‐treated participants (Analysis 9.6; Analysis 9.7; Analysis 9.8; Analysis 9.9; Analysis 9.10; Analysis 9.11; Analysis 9.12; Analysis 9.13; Analysis 9.14; Analysis 9.15; Analysis 9.16). Moreover, no difference was detected between the different 5‐fluorouracil treatment durations (Analysis 10.4; Analysis 10.5; Analysis 10.6; Analysis 10.7; Analysis 10.8; Analysis 10.9; Analysis 10.10; Analysis 10.11; Analysis 10.12).
To summarise, 5‐fluorouracil was more efficient than vehicle to treat actinic keratoses. Four‐week treatment gave better results than one‐ and two‐week treatments, which were comparable. Treatment with 0.5% 5‐fluorouracil for 4 weeks could lead to more adverse events as shown by the number of withdrawals due to adverse events. Significant facial irritation was associated with 0.5% 5‐fluorouracil treatment.
Different concentrations of 5‐fluorouracil
This intervention was addressed by one study (Loven 2002), which used a right/left withinparticipant design (intraindividual) to compare the efficacy of 0.5% to 5% 5‐fluorouracil cream or the treatment of actinic keratoses on the face, anterior bald scalp, or forehead. The creams were applied once daily on 1 side of the face with 0.5% cream and twice daily on the other side with 5% cream for 4 weeks. Assessment was performed at 4 weeks after the end of treatment. There was possible performance and reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 21 participants) | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 21 participants) |
| ‐ | x | ‐ | Absolute values and percentages |
Due to the intraindividual design of the study, no analysis could be performed for the participant‐based outcome 'participant complete clearance'; however, a similar total clearance rate was obtained for the 2 treatments, i.e. approximately 43% (9/21) (Loven 2002).
After treatment with 0.5% 5‐fluorouracil, participants had a mean reduction of 8.8 lesions, corresponding to 67%, and after 5% 5‐fluorouracil, the mean reduction was 6.1 (47%). The authors reported a significant difference (P = 0.044) between the 2 treatments for the absolute mean reduction in lesion counts and graphically represented the standard deviations associated with lesion counts at baseline and week 8. An analysis could not be performed because the numerical values of the standard deviations were not provided.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 21 participants) | Skin irritation (N = 21 participants) | Minor adverse events excluding skin irritation (N = 21 participants) | Cosmetic outcome |
| x | x | x | ‐ |
Sixteen of 21 participants discontinued treatment but did not withdraw from the study, because of irritation: 4 participants discontinued because of treatment with 0.5% 5‐fluorouracil cream, 8 because of 5% cream, and 4 because of both creams.
All participants reported facial irritation in association with both creams.
Eye irritation was reported in 5 out of 21 participants and nasal congestion in 3 out of 21 participants. It was not mentioned if these events were associated with a particular treatment side.
To summarise, 0.5% 5‐fluorouracil cream might be more efficient than the 5% cream and is associated with similar skin irritation.
5‐fluorouracil with tretinoin
This intervention was addressed by 1 intraindividual study (Bercovitch 1987) comparing 5% fluorouracil treatment combined with 0.05% tretinoin and 5% fluorouracil treatment combined with placebo for treatment of actinic keratoses. 5% fluorouracil was applied twice daily on both forearms and hands, and 0.05% tretinoin cream was applied nightly on a randomised forearm/hand and placebo on the other forearm/hand up to 12 weeks. Assessment was performed at the end of the 12‐week treatment. There was possible reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 20 participants) |
| ‐ | ‐ | ‐ | Absolute values |
The additional treatment with tretinoin did not make any difference in the mean reduction of lesion counts by 5% fluorouracil (Analysis 12.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 20 participants) | Skin irritation (N = 20 participants) | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | x (relative) | ‐ | ‐ |
Twelve participants experienced more irritation on the side treated with tretinoin cream, four on the side treated with placebo, and three had equal irritation. One participant withdrew from the study due to irritation, but it was not mentioned if it was due to one treatment in particular.
To summarise, additional treatment with tretinoin did not improve the efficacy of the 5‐fluorouracil treatment and was associated with more skin irritation.
5‐fluorouracil versus imiquimod
This comparison is discussed in the imiquimod section below, and the results presented in Table 2 correspond to Analysis 13.1.
5‐fluorouracil versus masoprocol
This intervention was addressed by 1 study (Kulp‐Shorten 1993), comparing 5% 5‐fluorouracil and 10% masoprocol for the treatment of actinic keratoses. Both creams were applied twice daily for four weeks on the head or neck. Assessment was performed four weeks after the end of treatment. There was possible bias (other) associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 57 participants) | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 49 participants) |
| Investigator | ‐ | ‐ | Absolute values and percentages |
Analysis of 'investigator global improvement indices' for cleared participants showed a strong and significant risk ratio favouring 5‐fluorouracil over masoprocol treatments (RR 3.60, 95% CI 1.57 to 8.26; Analysis 15.1). Two (NTT = 2.1) participants need to be treated to result in 1 clearance with 5‐fluorouracil, whereas a larger number would be needed for masoprocol.
No significant difference was detected with the absolute values for mean reduction in lesion counts (Analysis 15.2). In contrast, the mean percentages were significantly different and supported the superiority of 5‐fluorouracil in the treatment of actinic keratoses (MD 20.00, 95% CI 11.82 to 28.18; Analysis 15.3).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 57 participants) | Skin irritation | Minor adverse events excluding skin irritation (N = 57 participants) | Cosmetic outcome |
| x | ‐ | Graph | ‐ |
Only 1 participant in the 5‐fluorouracil group withdrew because of adverse events (Analysis 15.4).
Minor adverse events were presented graphically based on their severity as percentages of participants experiencing different adverse events, such as necrosis and contact dermatitis. Based on these data and the incidences of these events, the authors concluded that masoprocol treatment was better tolerated than the 5‐fluorouracil treatment, and they made a correlation with the number of participants that failed to complete 28 days of treatment. Indeed, a significantly higher percentage (65.5%) of participants treated with 5‐fluorouracil failed to complete 28 days of treatment than participants treated with masoprocol (16%).
To summarise, 2 out of 3 efficacy outcome measurements supported the superiority of 5% 5‐fluorouracil treatment over 10% masoprocol treatments for actinic keratosis. Masoprocol treatment may be associated with better tolerability.
Other comparisons
The comparisons between 5‐fluorouracil and cryotherapy, photodynamic therapy, resurfacing, and chemical peel are discussed in their respective sections. The results presented in Table 2 correspond to the following analyses:
1) cryotherapy (Analysis 14.1);
2) photodynamic therapy (Analysis 11.1; Analysis 11.2);
3) carbon dioxide laser resurfacing (Analysis 16.1; Analysis 16.2);
4) Er:YAG laser resurfacing (Analysis 17.1; Analysis 17.2); and
5) trichloroacetic acid peel (Analysis 18.1).
β‐1,3‐D‐glucan
This intervention was addressed by one study (Tong 1996), which compared β‐1,3‐D‐glucan with placebo for the treatment of solar keratoses. β‐1,3‐D‐glucan was applied twice daily for 7 days to 1 arm with placebo on the other arm. Assessment was performed seven weeks after the end of treatment. There was possible reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 20 participants) |
| ‐ | ‐ | ‐ | Absolute values |
The mean number of lesions at baseline were respectively 22.5 and 23.9, and the mean reductions after 8 weeks were 5.7 and 8.3 for β‐1,3‐D‐glucan and placebo treatment. Based on the graphical representation of the data (means and standard deviations) over time provided by the authors, β‐1,3‐D‐glucan treatment was not more effective than placebo at reducing actinic keratosis lesions. A statistical analysis was not possible because the numerical values of the standard deviations were not given by the authors.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 20 participants) | Skin irritation | Minor adverse events excluding skin irritation (N = 20 participants) | Cosmetic outcome |
| x (none lost) | ‐ | x | ‐ |
There were no participant withdrawals due to adverse events.
The participants did not report any minor adverse events.
To summarise, β‐1,3‐D‐glucan treatment showed no benefits in treating solar keratoses.
Imiquimod cream
Imiquimod versus placebo
This intervention was addressed by 18 studies (Alomar 2007; Chen 2003; Gebauer 2009; Hanke 2010; Jorizzo 2007; Jorizzo 2010; Korman 2005; Lebwohl 2004; NCT00828568 Taro; NCT00828568 Taro; Persaud 2002; Ooi 2006; Ortonne 2010; Stockfleth 2002; Swanson 2010a; Szeimies 2004; Ulrich 2007; Zeichner 2009) comparing 2.5% to 5% imiquimod cream and placebo in the treatment of actinic keratoses. Two studies had an intraindividual design (Persaud 2002; Zeichner 2009), whereas all the other studies had a parallel design. In only one study the participants were immunosuppressed (organ transplant patients, Ulrich 2007). Dosing regimens were varied and included 2.5%, 3.75%, and 5% imiquimod and 8 dosing regimens with and without repetition of the treatment schedule, which are summarised in the following table. There were possible performance (Gebauer 2009; Hanke 2010; Ortonne 2010), detection (Hanke 2010; Jorizzo 2007; Ortonne 2010), attrition (Chen 2003; Lebwohl 2004; Persaud 2002; Szeimies 2004; Zeichner 2009), reporting (Alomar 2007; Jorizzo 2007; Jorizzo 2010; Korman 2005; Lebwohl 2004; Persaud 2002; Szeimies 2004; Ulrich 2007), and other (Jorizzo 2007) biases.
| Study | Anatomical locations | Imiquimod percentage | Number of doses/week | Number of weeks | Number of doses | Time of assessment |
| Face, arms, legs | 5 | 3 | 8 or less | 24 or less | 8 weeks after the end of treatment | |
| Face, scalp, forehead, dorsal forearm, neck, back of hands | 5 | 3 | 12 or less | 36 or less | At the end of the 12‐week treatment | |
| Face, forehead and temples, cheeks | 5 | 3 | 3 or 6 | 9 or 18 | 4 weeks after the end of treatment | |
| Face or scalp | 5 | 2 | 16 or less | 32 or less | 8 weeks after the end of treatment | |
| Face or bald scalp | 5 | 3 | 16 or less | 48 or less | 8 weeks after the end of treatment | |
| Face or bald scalp | 5 | 3 | 16 | 48 | 8 weeks after the end of treatment | |
| Scalp, extremities, or upper trunk | 5 | 3 | 16 or less | 48 or less | At the end of treatment | |
| Face or bald scalp | 5 | 3 | 4 or 8 | 12 or 24 | 4 weeks after the end of treatment | |
| Head | 5 | 3 | 4 or 8 | 12 or 24 | 4 weeks after the end of treatment | |
| Face, forehead, or bald scalp | 5 | 3 | 16 | 48 | 8 weeks after the end of treatment | |
| Dorsal of 1 or both forearms and hands | 5 | 2,3,5,7 | 8 | 16,24,40,56 | 8 weeks after the end of treatment | |
| Head | 5 | 1 | 24 | 24 | 4 weeks after the end of treatment | |
| Face or bald scalp | 2.5, 3.75 | 7 | 6 (3 on, 3 off, 3 on) | 42 | 8 weeks after the end of treatment | |
| Face | 3.75 | 7 | 4 (2 on, 2 off, 2 on) | 28 | 20 weeks after the end of treatment | |
| Head (bald scalp or face) | 5 | 3 | 8 (4 on, 4 off, 4 on) | 24 | At week 20 (6 weeks after the end of treatment) | |
| Face or bald scalp | 2.5, 3.75 | 7 | 4 (2 on, 2 off, 2 on) | 28 | 8 weeks after the end of treatment | |
| Face or bald scalp | 5 | 2 | 16 | 32 | 8 weeks after the end of treatment | |
| Face or bald scalp | 5 | 2 | 16 | 32 | 8 weeks after the end of treatment |
Three types of subgroup analyses were performed: 1) by number of doses (from 9 to 56 doses) for 5% imiquimod (in the Analyses 19); 2) by imiquimod concentrations (in the Analyses 20); and 3) by frequency of application, i.e. number per week (in the Analyses 21).
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 20 participants) | Participant complete clearance (N = 3637 participants) | Participant partial (> 75%) clearance (N = 2914 participants) | Mean reduction in lesion counts (N = 315 participants) |
| ‐ | ‐ | ‐ | Absolute values | |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | x | Absolute values | |
| ‐ | x | x | ‐ | |
| ‐ | x | x | ‐ | |
| ‐ | x | x | ‐ | |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | x | ‐ | |
| ‐ | x | x | ‐ | |
| ‐ | x | x | ‐ | |
| ‐ | x | x | ‐ | |
| Investigator | ‐ | ‐ | ‐ | |
| ‐ | x | x | ‐ | |
| ‐ | x | ‐ | Percentages | |
| ‐ | ‐ | ‐ | Absolute values | |
| ‐ | x | x | ‐ | |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | ‐ | ‐ |
Only one intraindividual study, Zeichner 2009, presented the number of participants with global improvement indices for complete clearance. One participant out of 15 was completely cleared on the imiquimod‐treated side, whereas none of the participants showed complete clearance on the placebo‐treated side. Thus, this dosing regimen was not very effective.
Overall, the risk ratio for participant complete clearance favoured 5% imiquimod treatment over placebo for immunocompetent (RR 6.91, 95% CI 4.25 to 11.26; Analysis 19.1) as well as in immunosuppressed participants (RR 18.50, 95% CI 1.19 to 286.45; Analysis 19.2). Eight immunocompetent participants (NNT = 7.7) must be treated with 5% imiquimod to obtain 1 complete clearance. No immunosuppressed participant in the control group was completely cleared, so the corresponding number, i.e. NNT could not be calculated for this population.
However, 5% imiquimod was not statistically favoured in 4 of the 8 dosing regimens: 9 or 18 doses (3 times/week for 3 weeks on, 4 weeks off), 24 doses (3 times/week for 8 weeks), 40 doses (5 times/week for 8 weeks), and 56 doses (7 times/week for 8 weeks). Increasing the number of doses did not result in an increase in the values of the RRs, suggesting that the number of doses might not be a determining factor for the efficacy of imiquimod. Despite these subgroup analyses, substantial heterogeneity was associated with most of the subgroups of pooled studies. The heterogeneity was particularly high (I² statistic = 91%) for the 2 studies, with 1 or 2 courses 3 times/week for 4 weeks on, 4 weeks off, 4 weeks on (Alomar 2007; Jorizzo 2007). The two studies were similar in design. Alomar 2007 was performed in Europe and included participants with five to nine lesions, whereas Jorizzo 2007 was performed in North America and included participants with four to eight lesions. In the European study, 47/126 participants were cleared after 1 course and did not receive a second course, compared to 32/121 in the American study. This difference might explain the heterogeneity associated with these studies.
Slightly different results were obtained for participant partial (> 75%) clearance (Analysis 19.3). One additional dosing regimen did not reach significant difference (12 or 24 doses, 4 weeks on, 4 weeks off). In immunosuppressed participants, the results for partial clearance (RR 23.50, 95% CI 1.53 to 360.94; Analysis 19.4) were similar to complete clearance (Analysis 19.2).
The number of participants with complete clearance was significantly higher in the imiquimod‐treated group than the placebo‐treated group for the 3 concentrations, i.e. 2.5% (RR 4.49, 95% CI 2.40 to 8.39, NNT = 4.6), 3.75% (RR 6.45, 95% CI 3.87 to 10.73, NNT = 3.7), and 5% (RR 7.70, 95% CI 4.63 to 12.79, NTT = 4.7). Based on the result for the subgroup difference test (P = 0.42; Analysis 20.1), the efficacy of the 3 concentrations compared to placebo was not significantly different despite the fact that the magnitude of the effect increased with the concentration of imiquimod used to treat the actinic keratoses. In contrast, the analysis of the participant partial clearance, which included fewer studies, showed a significant difference between the concentrations of imiquimod (test for subgroup differences: P = 0.01; Analysis 20.2). It is also worth noting that the two studies (Gebauer 2009; Ooi 2006) not including lesions on the face did not favour imiquimod (Analysis 20.1).
The amplitude of the clearance effect increased when the frequency of application was increased from 2 to 3 times per week for both complete clearance (Analysis 21.1) from (RR 5.36, 95% CI 2.03 to 14.16) to (RR 8.38, 95% CI 3.79 to 18.52) and for partial clearance (Analysis 21.2) from (RR 4.99, 95% CI 3.43 to 7.26) to (RR 7.65, 95% CI 2.51 to 23.32), but the difference between the RRs between 2 and 3 times were not significantly different.
Also, no correlation was found for the subgroup analysis of the number of weeks of treatment (not shown).
A funnel plot (Figure 3) for all the studies reporting 'participant complete clearance' suggests that there was no publication bias for this outcome.
Funnel plot of comparison: 15 Imiquimod versus placebo: different concentrations, outcome: 15.1 Participant complete clearance.
Two studies (Ortonne 2010; Persaud 2002) with 24 doses of 5% imiquimod or placebo presented mean reduction in lesion counts as absolute values. Ortonne 2010, but not Persaud 2002, provided the associated standard deviations allowing statistical analysis. The mean reduction in lesion counts were similar for the imiquimod group (2.8 + 2.1 and 3.9) and for the placebo group (0.6 + 2.6 and 0.5), but the RR did not significantly favour imiquimod based on Ortonne 2010 alone (Analysis 19.5). In contrast, the mean percentage of reduction in lesion counts provided by Jorizzo 2010 with 3.75% imiquimod supported the superiority of imiquimod over placebo for treatment of actinic keratoses (MD 46.90, 95% CI 36.68 to 57.12; Analysis 20.3).
Secondary outcomes
In the Jorizzo 2010 study, some lesions also had cryotherapy treatment, and safety outcomes were only reported for the comparison between cryotherapy with and without imiquimod treatment. Thus, this study was not included in the secondary outcomes presented in this section.
| Study | Withdrawal due to adverse events (N = 3444 participants) | Skin irritation (N = 1677 participants) | Minor adverse events excluding skin irritation (N = 700 participants) | Cosmetic outcome (N = 1691 participants) |
| x (none lost ‐ intraindividual not included) | ‐ | ‐ | ‐ | |
| x (none lost) | ‐ | ‐ | ‐ | |
| x (none lost) | ‐ | ‐ | ‐ | |
| x | ‐ | ‐ | x | |
| x | x | ‐ | x | |
| x | ‐ | ‐ | x (imiquimod, not included) | |
| x (none lost) | ‐ | x | ‐ | |
| x | ‐ | ‐ | ‐ | |
| x | ‐ | ‐ | ||
| x | ‐ | x (imiquimod only, not included) | x (qualitative, not included) | |
| x | ‐ | x | ‐ | |
| x (none lost ‐ intraindividual not included) | Qualitative (not included) | ‐ | ‐ | |
| x | x | x | x | |
| x (none lost) | ‐ | ‐ | ‐ | |
| x | x | ‐ | x | |
| x | x | ‐ | ‐ | |
| x | x | ‐ | ‐ |
All of the studies reported the number of participants who withdrew because of adverse events. Six out of 17 studies reported that no participants withdrew due to adverse events (i.e. "none lost" in the previous table), which are not included in the pooled risk ratio of meta‐analysis because of the absence of events. All these studies used 5% imiquimod applied 3 times per week and had a very small sample size (< 50 participants) compared to the other studies. Thus, we have to be careful about the interpretation of the analysed data. When comparing 5% imiquimod application to placebo, there was no significant difference in withdrawals due to adverse effects except at 48 doses. At 48 doses, when 2 studies were combined, there was a significant difference in favour of placebo (RR 2.69, 95% CI 1.48 to 4.90, NNT=16.7; Analysis 19.6).
When 8 of the studies using 5% imiquimod were pooled together (imiquimod N = 1338, placebo N = 952), the number of participant withdrawals due to adverse events was significantly higher in the 5% imiquimod‐treated group than the placebo‐treated group (RR 2.59, 95% CI 1.59 to 4.23, NNT = 27; Analysis 20.5). The 4 studies with a parallel design (Chen 2003; Ooi 2006; Ortonne 2010; Stockfleth 2002), not included in the calculation of the pooled RR because of the lack of event, represented only 79 participants in the imiquimod group and 31 participants in the placebo group. Thus, we could conclude that 5% imiquimod treatment results in a higher number of participants withdrawn because of adverse events compared to placebo. In contrast, there was no significant difference for 3.75% and 2.5% imiquimod compared to placebo (Analysis 20.5).
For all frequencies of weekly application, there was a tendency to have more participants withdraw because of adverse events in the imiquimod group; a significant difference (RR 2.47, 95% CI 1.42 to 4.30, NTT = 27.2; Analysis 21.3) was reached in the 3 times per week group. Five studies (imiquimod N = 670, placebo N = 649) were included in the calculation of the pooled risk ratio, but 4 smaller studies were not included because of absence of withdrawal in the intervention and control arms (imiquimod N = 79, placebo N = 31). Finally, there was no difference in the number of participants who withdrew because of adverse events in the immunosuppressed participants (Analysis 19.7).
In the studies reporting skin irritation, no significant difference was observed for the separate analysis of the different concentrations. However, the pooled risk ratio did favour placebo, i.e. more participants treated with imiquimod experienced skin irritation compared to participants treated with placebo (RR 3.93, 95% CI 1.56 to 9.88, NNT = 60; Analysis 20.6). In the intraindividual study Zeichner 2009, the participants experienced similar mild irritation with 5% imiquimod and placebo.
Only one study, Gebauer 2009, reported the number of participants experiencing 'minor adverse events excluding skin irritation' in general for different body systems, i.e. body as a whole, digestive system, and nervous system. None of the data were significantly different between the 5% imiquimod‐ and placebo‐treated groups. Few studies reported the number of participants experiencing specific minor adverse events. The following adverse events affecting the body as a whole (pyrexia), the haemic and lymphatic system (lymphadenopathy), the musculoskeletal system (myalgia), the nervous system (fatigue), the respiratory system (cough, sinusitis, and upper respiratory tract infection), and the urogenital system (urinary tract infection) were not different between imiquimod and placebo groups. The number of participants treated with imiquimod experiencing "flu" or "cold"‐like symptoms or "headache" was generally not different from placebo‐treated participants except for application 7 times per week reported in 1 study by Hanke 2010 (RR 19.68, 95% CI 1.20 to 323.89; Analysis 21.5).
Only a few studies gave quantitative cosmetic outcomes (Lebwohl 2004; Szeimies 2004); a significant decrease in roughness, dryness, and scaliness of the skin was associated with 5% imiquimod treatment compared to placebo (RR 3.23, 95% CI 1.86 to 5.58, NNT = 2.6; Analysis 19.13). In addition, overall cosmetic outcomes were significantly or much improved with 2.5% (RR 2.25, 95% CI 1.62 to 3.14, NNT = 3.1) and 3.75% (RR 2.71, 95% CI 2.05 to 3.58, NNT = 2.3) imiquimod compared to placebo (Analysis 20.16).
To summarise, the efficacy of imiquimod compared to placebo was significantly better based on the participant complete and partial clearance as well as the mean percentage of reduction in lesion counts, but not for the absolute mean reduction in lesion counts. The amplitude of the effect was independent of the number of doses of 5% imiquimod, imiquimod concentrations, or frequency of application on a weekly basis. The number of withdrawals due to adverse events in the imiquimod group compared to placebo was statistically significant in the 48‐dose group (although not in the 56‐dose group) compared with the lower doses and in the 5% compared to the 2.5% and 3.75% imiquimod concentrations. Significantly better cosmetic outcomes were obtained with imiquimod treatment.
Imiquimod versus diclofenac
This comparison was reported in the diclofenac section above.
Imiquimod versus 5‐fluorouracil
This intervention, which was addressed by 2 studies, 1 assessor‐blinded (Tanghetti 2007) and 1 open study (Krawtchenko 2007), compared the efficacy of 5% imiquimod and 5% 5‐fluorouracil for the treatment of actinic keratoses. In Krawtchenko 2007, imiquimod was applied on the head, neck, or décolleté 3 times per week for 4 weeks on and 4 weeks off, once or twice, and 5‐fluorouracil was applied twice daily for 4 weeks. Assessment was performed 4 and 8 weeks after the end of treatment for 5‐fluorouracil and imiquimod, respectively. Tanghetti 2007 applied imiquimod on the face, forehead, or scalp twice weekly for 16 weeks and 5‐fluorouracil twice daily for 2 to 4 weeks. Assessment was performed at 8 weeks after the end of treatment. There were possible performance (Krawtchenko 2007; Tanghetti 2007), detection (Krawtchenko 2007), and reporting (Tanghetti 2007) biases.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 89 participants) | Participant partial (> 75%) clearance | Mean reduction in lesion counts (N = 50 participants) |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | ‐ | Percentages |
With regard to the outcome 'participant complete clearance', no pooled RR can be calculated because of the high heterogeneity (I² statistic = 93%; Analysis 22.1) associated with the 2 studies. The data from Krawtchenko 2007, which had no blinding specified, did not favour any treatment (RR 0.88, 95% CI 0.73 to 1.06). In contrast, the data from Tanghetti 2007, which was assessor‐blinded, significantly favoured 5‐fluorouracil (RR 0.31, 95% CI 0.14 to 0.67). The variability in the dosing regimen might explain the considerable heterogeneity associated with participant complete clearance. Tanghetti 2007 also supported 5‐fluorouracil superiority by reporting the mean percentage of reduction in lesion counts of 94% and 66% for 5‐fluorouracil and imiquimod, respectively. However, the authors did not provide the standard deviation associated with these values to determine statistically the significance of this difference between the treatments.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 89 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (N = 50 participants) |
| x (none lost) | ‐ | ‐ | ‐ | |
| x (none lost) | ‐ | ‐ | x |
There were no participant withdrawals due to adverse events.
The percentage of participants with a general cosmetic outcome assessed as excellent by the investigator was clearly better for imiquimod (21/26 = 81%) than 5‐fluorouracil (1/24 = 4%) (RR 19.38, 95% CI 2.82 to 133.26, NNT = 1.3; Analysis 22.2). Moreover, the skin quality was better in the imiquimod group than the 5‐fluorouracil group (RR 1.45, 95% CI 1.00 to 2.11, NNT = 3.8; Analysis 22.3).
To summarise, the superiority of 5‐fluorouracil over imiquimod in treating actinic keratoses needs to be supported by additional data. Imiquimod treatment seemed to result in better cosmetic outcomes than 5‐fluorouracil.
Other comparisons
The efficacy of imiquimod compared with cryotherapy will be discussed in the cryotherapy section below, and the results presented in the additional Table 5 correspond to Analysis 23.1. Similarly, comparison with photodynamic therapy will be discussed in the phototherapy section.
Ingenol mebutate (PEP005)
This intervention was addressed by three studies (Anderson 2009; Siller 2009; Swanson 2010b). These three studies investigated the efficacy of ingenol mebutate applied once daily for two to three consecutive days or once weekly for two weeks, i.e. two days one week apart (Siller 2009), compared to vehicle for the treatment of actinic keratoses. Treatments were applied to the arms, shoulder, chest, and scalp in both Anderson 2009 and Siller 2009. In addition, the treatments were also applied to the back in Anderson 2009 and the face in Siller 2009, whereas only non‐head locations were investigated in Swanson 2010b. Assessment was performed 8 (Anderson 2009; Swanson 2010b) and 12 (Siller 2009) weeks after the first day of treatment. There was possible reporting (Anderson 2009) and other (Siller 2009) bias.
Because different concentrations (0.025%, 0.01%, and 0.05%) of ingenol mebutate and dosing regimens were used in these studies, subgroup analyses were performed for the different ingenol mebutate concentrations (in the Analyses 25) and the number of applications for 0.05% ingenol mebutate (i.e. number of doses or days, in the Analyses 26). Analyses of pooled data were also performed (in the Analyses 24).
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 477 participants) | Participant partial (> 75%) clearance (N = 285 participants) | Mean reduction in lesion counts |
| ‐ | x | x | ‐ | |
| ‐ | ‐ | x | ‐ | |
| ‐ | x | x (percentage not specified and data not included in analysis) | ‐ |
Participant complete clearance was evaluated for target lesions (i.e. present at baseline) as well as for all lesions (i.e. target and new lesions). For both, the number of participants completely cleared was significantly higher in the ingenol mebutate group compared to vehicle (target: RR 3.61, 95% CI 1.86 to 7.02, NNT = 2.9; Analysis 24.1) (all lesions: RR 4.50, 95% CI 2.61 to 7.74, NNT = 3.4; Analysis 24.2), which corresponds to 383 per 1000 participants for ingenol mebutate and 73 per 1000 participants for vehicle achieving complete clearance.The amplitude of the effect had a tendency to increase with the concentration of ingenol mebutate (Analysis 25.1; Analysis 25.2), but not with the number of applications of 0.05% ingenol mebutate (Analysis 26.1; Analysis 26.2).
Similar results were obtained for participant partial clearance with a RR of 2.88, 95% CI 1.81 to 4.58 (Analysis 24.3), corresponding to a NNT of 2.8. A possible dependence on the ingenol mebutate concentration (Analysis 25.3), but not on the number of applications for 0.05% ingenol mebutate (Analysis 26.3), was also observed.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 540 participants) | Skin irritation | Minor adverse events excluding skin irritation (N = 222 participants) | Cosmetic outcome (N = 540 participants) |
| x | ‐ | x | ‐ | |
| x | ‐ | ‐ | x | |
| x | ‐ | ‐ | x |
No withdrawal due to adverse events was reported in Anderson 2009 and Siller 2009. However, in Swanson 2010b, 1 out of 255 participants withdrew because of an adverse event (pain), but the associated treatment was not specified.
No statistical analyses were performed for minor adverse events because only one participant experienced the individual minor adverse events reported, as shown in the following table, and no statistical significance could be reached. However, based on the incidences, more reports of minor adverse events were associated with the 0.05% ingenol mebutate.
| Body system | Minor adverse event | Placebo (N = 60) | 0.025% ingenol mebutate for 3 days (N = 50) | 0.05% ingenol mebutate for 3 days (N = 57) | 0.05% ingenol mebutate for 2 days (N = 55) |
| Body as a whole | Chills | 0 | 0 | 1 | 0 |
| Body as a whole | Fever | 0 | 0 | 0 | 1 |
| Body as a whole | Flu or cold | 0 | 0 | 0 | 1 |
| Dermatologic | Contact dermatitis | 0 | 0 | 1 | 0 |
| Dermatologic | Impetigo | 0 | 0 | 1 | 0 |
| Hemic and lymphatic | Traumatic hematoma | 0 | 0 | 1 | 0 |
| Metabolic and nutritional disorders | Increase in creatine phosphokinase | 0 | 0 | 0 | 1 |
| Musculoskeletal and connective tissue | Muscle spasms | 1 | 0 | 0 | 1 |
| Nervous system | Headache | 0 | 0 | 1 | 0 |
| Renal and urogenital | Proteinuria | 0 | 0 | 0 | 1 |
| Respiratory | Nasal congestion | 0 | 1 | 0 | 0 |
| Incidences | |||||
| Each treatment arm | 1 | 1 | 5 | 5 | |
| 3 days versus 2 days | 6 | 5 | |||
| 0.025% versus 0.05% | 1 | 10 | |||
There was no scarring, but some pigmentation changes occurred in some participants treated with ingenol mebutate. These changes were not significantly different compared to vehicle (Analysis 24.4).
To summarise, ingenol mebutate was significantly more efficient than vehicle in treating actinic keratoses. When a higher concentration was used (i.e. 0.05%), ingenol mebutate generally resulted in better efficacy. Increasing the number of applications from two to three times did not result in an increase in the number of participants cleared. No significant difference was observed between ingenol mebutate and placebo for adverse events. Thus, ingenol mebutate treatment was relatively safe and efficient for actinic keratosis treatment.
Isotretinoin
This intervention was addressed by 1 study (Alirezai 1994) comparing the efficacy and safety of 0.1% isotretinoin and vehicle cream applied twice daily for 24 weeks for the treatment of actinic keratoses of the face, scalp, and upper extremities. Assessment was performed at the end of treatment. There was possible attrition and other bias in this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 100 participants) | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction (changes) in lesion counts (N = 100 participants) |
| Investigator | ‐ | ‐ | Absolute values |
The number of participants experiencing complete clearance, partial clearance, no clearance, and worsening were determined by an investigator global evaluation at the end of treatment. The numbers of participants with complete clearance were low with both isotretinoin and placebo for the three anatomical locations, and the associated risk ratios did not favour any treatment (Analysis 27.1).
The mean reduction of lesion counts for lesions on the face (MD 2.20, 95% CI 1.97 to 2.43) and upper extremities (MD 1.90, 95% CI 1.28 to 2.52), but not on the scalp, did favour isotretinoin over placebo (Analysis 27.2).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 100 participants) | Skin irritation (N = 92 participants) | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | x (in general and severe) | ‐ | ‐ |
Two of 50 participants in the isotretinoin group withdrew because of adverse events, but it was not statistically different compared to the placebo group (0/50) (Analysis 27.3).
Local irritation on the face, but not on the scalp or upper extremities (Alirezai 1994), was significantly more frequent for the isotretinoin‐treated group than for the placebo‐treated group for all intensities (RR 1.57, 95% CI 1.23 to 2.01, NNT = 3.0; Analysis 27.4) as well as severe irritation (RR 17.09, 95% CI 2.35 to 124.10, NNT = 3.1; Analysis 27.5).
To summarise, 0.1% isotretinoin with the dosing regimen used was able to significantly reduce actinic keratoses counts on the face or upper extremities but was not sufficient to result in significant participant complete clearance. Isotretinoin treatment was associated with significant local irritation on the face.
Masoprocol
Masoprocol versus vehicle
This intervention was addressed by 1 study (Olsen 1991) comparing 10% masoprocol cream to vehicle cream for the treatment of actinic keratoses. Masoprocol or placebo creams were applied on the head and neck once or twice daily for a maximum of 28 days and follow‐up assessment was done at 4 weeks after the last application of the study drug. There was possible attrition and other bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 154 participants) | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction in lesion counts (N = 154 participants) |
| Investigator | ‐ | ‐ | Absolute values |
Masoprocol‐treated participants had a complete cure rate of 12/113 (11%), which was similar to the cure rate of the vehicle cream; 2/41 (5%), as globally assessed by the investigator. Thus, the RR associated with investigator global improvement indices for cured participant did not significantly favour masoprocol.
In contrast, mean reduction in lesion counts was significantly higher for masoprocol than for vehicle‐treated groups (MD 7.30, 95% CI 5.77 to 8.83; Analysis 28.2).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 176 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | ‐ | ‐ | ‐ |
Two of 131 participants in the masoprocol group withdrew because of adverse events, but it was not statistically different to the placebo group (0/45) (Analysis 28.3).
To summarise, 10% masoprocol with the dosing regimen used was able to significantly reduce actinic keratoses counts but was not sufficient to result in significant participant complete clearance as globally assessed by the investigator. Substantial local skin reactions were also associated with masoprocol treatment compared to vehicle.
Masoprocol versus 5‐fluorouracil
This comparison was presented in the 5‐fluorouracil section above.
Nicotinamide
This intervention was addressed by 1 study (Moloney 2010) investigating the efficacy of 1% nicotinamide twice daily compared to placebo for the treatment of non‐hyperkeratotic actinic keratoses on the face, scalp, and upper limbs. Assessment was performed at three and six months after the beginning of the treatment. There was possible reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean reduction in lesion counts (N = 30 participants) |
| ‐ | ‐ | ‐ | Percentages |
Mean percentage of reduction in lesion counts was assessed at three and six months. At 3 months, the associated RR favoured nicotinamide that reduced by 21.8 + 10% the number of lesions compared to 10 + 12% for placebo (MD 11.80, 95% CI 3.92 to 19.68; Analysis 29.1). The superiority of nicotinamide was lost at six months (Analysis 29.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 30 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | ‐ | ‐ | ‐ |
None of the 13 participants in the nicotinamide group withdrew because of adverse events; it was not statistically different to the placebo group, which had 2 withdrawals out of 17 participants (Analysis 29.2).
In summary, 1% nicotinamide had very limited short‐term efficacy at the dosing regimen used.
Resiquimod
This intervention was addressed by 1 study (Szeimies 2008) investigating different concentrations (0.01%, 0.03%, 0.06%, and 0.1%) of resiquimod for the treatment of actinic keratoses on the face or bald scalp. The cream was applied once daily three times per week for four weeks on and eight weeks off, once or twice, i.e. one or two treatment cycles depending on the participant response to treatment. Assessment was performed at eight weeks after the end of treatment. There was possible other bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 132 participants) | Participant partial (> 75%) clearance (N = 132 participants) | Mean reduction in lesion counts |
| ‐ | x | x | ‐ |
Results from individual analyses of participant complete and partial clearance for pairs of resiquimod concentrations are summarised in the following table.
| Higher versus lower resiquimod concentrations | |||
| Participant complete clearance (after 1 cycle) | Participant complete clearance (after 1 or 2 cycles) | Participant partial clearance (after 1 or 2 cycles) | |
| 0.1% vs 0.01% | > | > | > |
| 0.1% vs 0.03% | > | < | = |
| 0.1% vs 0.06% | > | > | > |
| 0.06% vs 0.01% | > | = | = |
| 0.06% vs 0.03% | < | < | < |
| 0.03% vs 0.01% | > | > | > |
< : significantly inferior, < : tendency to be inferior, = : equal, >: tendency to be superior, > : significantly superior, vs = versus
For participant complete clearance, the efficacy of 0.1% resiquimod was generally superior to the other lower concentrations after 1 treatment cycle (0.1% vs 0.01%: RR 2.45, 95% CI 1.64 to 3.65, NNT = 1.7; Analysis 30.1) (0.1% vs 0.03%: RR 1.34, 95% CI 1.09 to 1.66, NNT = 4.0; Analysis 31.1) (0.1% vs 0.06%: RR 1.76, 95% CI 1.30 to 2.38, NNT = 2.3; Analysis 32.1). After the second cycle of treatment, the differences between resiquimod concentrations were lost.
No significant difference was detected between the resiquimod concentrations used with the outcome 'participant partial clearance' (Analysis 30.2; Analysis 31.2; Analysis 32.2; Analysis 33.2; Analysis 34.2; Analysis 35.2).
In general, higher concentrations had a tendency to be more effective. The results obtained with 0.03% and 0.06% resiquimod suggest that these 2 concentrations might have been "switched" or "mislabelled" (Analysis 34.1; Analysis 34.2).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 132 participants) | Skin irritation | Minor adverse events excluding skin irritation (N = 132 participants) | Cosmetic outcome |
| x | ‐ | In general by body system and individual adverse event | ‐ |
There were significantly more participants in the 0.1% resiquimod group who withdrew because of adverse events compared to those in the 0.01% (RR 27.77, 95% CI 1.72 to 449.47, NNT = not applicable; Analysis 30.3) and 0.03% (RR 2.96, 95% CI 1.08 to 8.13, NNT = 4.0; Analysis 31.3) resiquimod groups. A significant difference was also found between 0.06% and 0.01% resiquimod (RR 22.91, 95% CI 1.40 to 375.77, NNT = not applicable; Analysis 33.3).
Results from individual analyses of minor adverse events excluding skin irritation for pairs of resiquimod concentrations are summarised in the following table.
| Minor adverse events excluding skin irritation | |||||||
| Higher versus lower resiquimod concentrations | |||||||
| Musculoskeletal and connective tissue (in general) | Nervous system (in general) | Skin and subcutaneous tissue disorders (in general) | |||||
| 0.1% vs 0.01% | > | > | > | ||||
| 0.1% vs 0.03% | > | = | > | ||||
| 0.1% vs 0.06% | = | = | < | ||||
| 0.06% vs 0.01% | > | > | > | ||||
| 0.06% vs 0.03% | > | = | > | ||||
| 0.03% vs 0.01% | > | > | < | ||||
| Body as a whole | Musculoskeletal and connective tissue | Nervous system | |||||
| Fatigue | Rigors | Arthralgia | Myalgia | Headache | Lethargy | Psychiatric disorders | |
| 0.1% vs 0.01% | > | > | > | > | > | > | > |
| 0.1% vs 0.03% | = | > | > | > | = | > | = |
| 0.1% vs 0.06% | > | < | < | > | = | = | < |
| 0.06% vs 0.01% | > | > | > | > | > | > | > |
| 0.06% vs 0.03% | < | > | > | = | = | > | > |
| 0.03% vs 0.01% | > | > | = | > | > | > | > |
< : significantly less participants, < : tendency to have less participants, = : equal number of participants, > : tendency to have more participants, > : significantly more participants
The numbers of participants experiencing adverse events related to musculoskeletal, connective tissue, and skin and subcutaneous tissue disorders, were similar between the different resiquimod concentrations. In contrast, the numbers of participants with adverse events associated with the nervous system in general were significantly lower in the 0.01% resiquimod group compared to all the other groups, which had similar number of participants (0.03%: RR 9.03, 95% CI 1.20 to 68.22, NNT = 4.3; Analysis 35.9) (0.06%: RR 10.94, 95% CI 1.48 to 80.73, NNT = 3.5; Analysis 33.9) (0.1%: RR 10.29, 95% CI 1.39 to 76.12, NNT = 3.7; Analysis 30.9). Headache, the only individual adverse event with significant difference between 2 resiquimod concentrations (0.06% vs 0.01%: RR 18.55, 95% CI 1.11 to 308.90, NNT = not applicable; Analysis 33.10), is a main contributor to the nervous system‐related adverse events in this study, with 6/8 participants in the 0.03% group, 8/10 in the 0.06% group, and 7/10 in the 0.1% group suffering from it.
To summarise, 0.1% resiquimod was more effective than the other lower concentrations only if the participants were treated with 1 cycle, i.e. once per day 3 times per week for 4 weeks on and 8 weeks off. Treatment with 0.01% resiquimod was generally associated with less adverse events compared to the other 3 concentrations used.
Sunscreen
Sunscreen is not generally a treatment for actinic keratosis, but it is a means of preventing actinic keratoses. However, one study investigated the role of sunscreen in the cure of existing lesions.
Sunscreen SPF 17 (8% 2‐ethyl‐hexyl p‐methoxycinnamate/2% 4‐tert‐butyl‐4‐methoxy‐4‐dibenzoylmethane) versus placebo
This intervention was addressed by one study (Thompson 1993) comparing sunscreen or placebo creams applied as needed daily for seven months to treat solar keratoses on the head, neck, forearms, and hands. Assessment was performed at the end of the seven‐month treatment. There was possible attrition bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 431 participants) |
| ‐ | ‐ | ‐ | Absolute values |
Mean changes [reduction (‐) or increase (+)] in lesion counts (Analysis 36.1) were assessed at the end of treatment. The sunscreen‐treated group showed a small mean decrease in lesion counts (‐0.6 + 4.34, SD), whereas the placebo‐treated group showed a mean increase in lesion counts (1 + 4.46, SD), demonstrating that sunscreen application could not only prevent but also treat actinic keratoses. The resulting mean difference of ‐1.60 (95% CI ‐2.43 to ‐0.77) favoured the use of sunscreen.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 588 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | ‐ | ‐ | ‐ |
The authors of the Thompson 1993 study mentioned that 28 and 32 participants in the placebo and sunscreen groups, respectively, withdrew from the study because of skin reactions. We were unable to perform statistical analysis as the participants who withdrew were not grouped by individual reason, and some participants had multiple reasons. Because the number of participants in each treatment group was similar for withdrawal due to skin reactions, withdrawal in general, and who completed the study, we can assume that there was no significant difference in the number of participants who withdrew because of adverse events between the placebo and sunscreen groups.
To summarise, sunscreen might help to treat actinic keratoses in addition to its preventive role, but the efficacy was limited.
DL‐α‐tocopherol (vitamin E)
This intervention was addressed by 1 study (Foote 2009) comparing 12.5% DL‐α‐tocopherol (vitamin E) and placebo applied twice daily for 6 months on the right/left arms for treatment of actinic keratoses. Assessment was performed at the end of the six‐month treatment. There was possible other bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 42 participants) |
| ‐ | ‐ | ‐ | Absolute values |
No significant difference in mean reduction in lesion counts (Analysis 37.1) was observed.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 48 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | ‐ | ‐ | ‐ |
In this intraindividual study, 2 of the 48 participants withdrew from the study because of unrelated illness.
To summarise, vitamin E at the dosing regimen used was not more efficient than placebo to treat actinic keratoses.
Tretinoin
Tretinoin with 5‐fluorouracil
This comparison was presented in the 5‐fluorouracil section above.
Tretinoin versus arotinoid methyl sulfone (Ro 14‐9706)
This comparison was presented in the arotinoid methyl sulfone section above
(2) Prescription‐based oral drugs
Only one intervention for the treatment of actinic keratoses was given orally: etretinate.
Etretinate
This intervention was addressed by one study (Moriarty 1982) investigating the efficacy of etretinate for the treatment of actinic keratoses by comparing it to placebo treatment. Two parts were involved in this double‐blind cross‐over study, and only the first part is presented in this review. The first part involved oral etretinate, a 225 mg tablet 3 times daily for 2 months for 1 group, and the other group taking placebo with the same regimen. Assessment was performed at the end of the two‐month treatment. The anatomical locations of the lesions analysed were not specified. There was possible attrition bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 50 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts |
| ‐ | x | ‐ | ‐ |
Complete remission rates (converted to participant complete clearance) after part 1 were better in the etretinate group (5/25 = 20%) compared to placebo (0/25 = 0%), but it was not statistically significant (RR 11.00, 95% CI 0.64 to 188.95; Analysis 38.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 50 participants) | Skin irritation | Minor adverse events excluding skin irritation (N = 50 participants) | Cosmetic outcome |
| x (maybe) | ‐ | x | ‐ |
Five (etretinate = 3, placebo = 2) participants out of 50 dropped out of the study, but the reasons were not specified.
Because the adverse events were reported for both parts of the study, the quantitative data were not included in this review. Adverse effects were consistent with vitamin A‐type side‐effects (i.e. dry mouth, skin rash, desquamation, etc) and were experienced within the first three to four weeks of starting treatment by a large number of participants, but were reversed by reducing dosage. Many participants (17/44 = 39%, at the end of the 2 parts of the cross‐over study) required reduction in dosage due to toxicity of etretinate (hepatotoxicity), but response was still maintained when dosage was reduced. Hyperlipidaemia (raised serum lipid levels) associated with etretinate was not assessed in this study.
To summarise, etretinate at the dosing regimen used was not statistically more efficient than placebo to treat actinic keratoses and was associated with adverse events.
(3) Mechanical interventions
The only mechanical intervention reported in the included studies was laser resurfacing, and the different types of laser resurfacing are presented in alphabetical order: carbon dioxide and Er:YAG laser resurfacing. Both interventions are field‐directed treatments.
Carbon dioxide laser resurfacing
This intervention was addressed by 1 study (Hantash 2006) comparing the efficacy of 2 passes of carbon dioxide laser resurfacing with 5‐fluorouracil applied twice daily for 3 weeks and with trichloroacetic acid peel in the treatment of actinic keratoses on the face. Assessment was performed at 12 weeks after the end of the treatment. There was possible performance, detection, and attrition bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 27 participants) |
| ‐ | ‐ | ‐ | Percentages |
The mean percentage of reduction in lesion counts showed a tendency to favour resurfacing compared to 5‐fluorouracil treatment (Analysis 39.1) or trichloroacetic acid peel (Analysis 40.1), but the differences were not statistically significant.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 27 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (N = 27 participants) |
| x | ‐ | ‐ | x |
Two of 8 participants in the carbon dioxide laser resurfacing group withdrew because of adverse events (incomplete treatment due to intolerance), whereas no participants withdrew in the trichloroacetic acid peel (0/10) and 5‐fluorouracil (0/9) groups. However, there was no statistically significant difference (Analysis 39.2; Analysis 40.2) between the treatments.
No postinflammatory pigmentary alteration or scarring was noted in the three treatment arms.
To summarise, the small sample size used in this study did not allow us to conclude on the superiority for efficacy or safety of carbon dioxide laser resurfacing over fluorouracil or trichloroacetic acid peel.
Er:YAG laser resurfacing
This intervention was addressed by 1 study (Ostertag 2006) comparing the efficacy of Er:YAG laser resurfacing and 5% 5‐fluorouracil applied twice daily for 4 to 7 weeks for the treatment of actinic keratoses on the face, scalp, or both. Assessments were performed at 3, 6, and 12 months after the end of treatment. There was possible reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 55 participants) |
| ‐ | ‐ | ‐ | Absolute values and percentages |
A statistical analysis could not be performed because the associated standard deviations were not provided with the mean reductions. The means in Analysis 41.1 suggested that the 2 treatments were equally efficient at reducing actinic keratosis lesions, whereas the mean percentages in Analysis 41.2 suggested better efficacy for laser resurfacing at 6 and 12 months. A statistical significance was stated by the authors.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 55 participants) | Skin irritation (N = 55 participants) | Minor adverse events excluding skin irritation (N = 55 participants) | Cosmetic outcome (N = 55 participants) |
| x | Overtime | Overtime | x |
One participant withdrew due to an adverse event (death) in the 5‐fluorouracil‐treated group, which was not significantly different to the Er:YAG laser resurfacing group (Analysis 41.3).
The adverse events (skin irritation and minor adverse events) could be categorised into 3 groups:
1) adverse events present only after treatment;
2) adverse events developing after the treatment, i.e. during the follow‐up period; and
3) adverse events present after the treatment and at follow‐up. Infection was present only at the end of the treatment.
The number of participants who developed an infection was not significantly different between the two treatments but was higher at most time points with laser resurfacing. Acne and milia developed during the follow‐up period. The number of participants with acne or milia was higher in the laser resurfacing group. The exception was acne at 12 months, which was similar between the two groups. The number of participants experiencing pain, crustea, and irritation tended to be higher in the fluorouracil treated‐group at the end of treatment, but it became higher in the laser resurfacing group during follow‐up. Only the number of participants with crustea was significantly different at the end of treatment (RR 0.46, 95% CI 0.27 to 0.79, NNT = 2.4; Analysis 41.6).
In terms of cosmetic outcomes, hypopigmentation got worse over time for laser resurfacing, significantly favouring 5‐fluorouracil at 12 months (RR 11.57, 95% CI 1.61 to 83.00; Analysis 41.10), corresponding to a NNT of 2.6 for an additional harmful outcome with laser re‐surfacing. Scarring was seen only in the laser resurfacing group but was not significantly different than in the fluorouracil group. In contrast, significantly more participants improved on the photoageing score with the laser resurfacing at 6 months (RR 1.57, 95% CI 1.01 to 2.43, NNT = 3.5) and 12 months (RR 1.70, 95% CI 1.01 to 2.88, NNT = 3.3) (Analysis 41.12) based on evaluation by 2 blinded investigators.
To summarise, the superiority of Er:YAG laser resurfacing over 5‐fluorouracil still needs to be demonstrated. More adverse events were associated with Er:YAG laser resurfacing compared to 5‐fluorouracil; however, overall ageing scores were better with Er:YAG laser resurfacing.
(4) Chemical interventions
Chemical interventions included studies on cryotherapy, photodynamic therapy, and trichloroacetic acid peel, which are presented in alphabetical order.
Cryotherapy
Cryotherapy was either compared with or combined with topical treatments or other chemical interventions, e.g. photodynamic therapy. Thus, the results are presented in two corresponding sections. Within each section, the comparisons are presented in alphabetical order of the comparison treatment. Cryotherapy is a lesion‐directed treatment for detectable lesions, whereas topical treatments are generally field‐directed treatments, which treat both detectable and subclinical lesions. Photodynamic therapy can be used for single lesion or field‐directed treatments. Cryotherapy and photodynamic therapy are provider‐administered, whereas topical treatments are administered by participants, and their efficacy is highly dependent on the compliance of the participants. These factors might influence the treatment efficacy.
Comparisons with topical treatments
Cryotherapy compared to betulin‐based oleogel
This intervention was addressed by one study (Huyke 2009) comparing cryotherapy with liquid nitrogen to betulin‐based oleogel alone on the face, scalp, or other locations. Cryotherapy of participant lesions was performed once on lesions on the face and twice on lesions on the rest of the body, whereas betulin‐based oleogel was applied twice daily for an unspecified duration. Assessment was performed at three months after the beginning of the treatment. There was possible performance and detection bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 30 participants) | Participant partial (> 75%) clearance (N = 30 participants) | Mean (changes) reduction in lesion counts |
| ‐ | x | x | ‐ |
Similar participant complete or partial (> 75%) clearance rates were observed for the 2 treatments (Analysis 42.1; Analysis 42.2).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 30 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x (none lost) | ‐ | ‐ | ‐ |
There were no participant withdrawals due to adverse events.
To summarise, the regimens used in this study for cryotherapy with liquid nitrogen and betulin‐based oleogel had similar efficacy for the treatment of actinic keratoses.
Cryotherapy compared to 5‐fluorouracil
This intervention was addressed by 1 study (Krawtchenko 2007) comparing cryotherapy with liquid nitrogen performed once or twice with 2‐week intervals to 5% 5‐fluorouracil applied twice daily for 4 weeks on the head, neck, and décolleté. Assessment was performed at 4 (5‐fluorouracil) or 6 (cryotherapy) weeks after the end of treatment and at 1‐year follow‐up. There was possible performance and detection bias.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 49 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts |
| ‐ | x | ‐ | ‐ |
5% 5‐fluorouracil was significantly more effective than cryotherapy to completely clear participants of lesions after the treatment (RR 0.71, 95% CI 0.54 to 0.94, NNT = 3.6) as well as at 12‐month follow‐up (RR 0.12, 95% CI 0.02 to 0.89, NNT = 3.4; Analysis 43.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 49 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (N = 49 participants) |
| x (none lost) | ‐ | ‐ | x |
There were no participant withdrawals due to adverse events.
The same percentage (4%) of the participants in the 5% 5‐fluorouracil group and cryotherapy group showed excellent cosmetic outcome as assessed by the investigator. Significantly more participants in the 5‐fluorouracil group had better skin appearance (RR 0.27, 95% CI 0.11 to 0.72, NNT = 2.3; Analysis 43.3).
To summarise, cryotherapy was less efficacious than 5% 5‐fluorouracil at treating actinic keratoses.
Cryotherapy compared to imiquimod
This intervention was addressed by 1 study (Krawtchenko 2007) comparing cryotherapy and 5% imiquimod. Cryotherapy was performed once or twice with a 2‐week interval, whereas imiquimod was applied 3 times per week for 4 weeks followed by 4 weeks rest, and repeated if needed. There was possible performance and detection bias.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 51 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts |
| ‐ | x | ‐ | ‐ |
No significant difference was found in the number of participants completely cleared between 5% imiquimod applied for a total of 4 weeks and cryotherapy treatments, but there were more participants with clearance with imiquimod (22//26 compared with 17/25 on cryotherapy), which may have been due to the additional treatment of subclinical lesions (RR 0.80, 95% CI 0.59 to 1.10; Analysis 44.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 51 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (N = 51 participants) |
| x (none lost) | ‐ | ‐ | x |
There were no participant withdrawals due to adverse events.
Assessment by the investigator showed that 4% and 81% of the participants had excellent cosmetic outcomes for cryotherapy and imiquimod treatments, respectively (RR 0.05, 95% CI 0.01 to 0.34, NNT = 1.3; Analysis 44.2). In particular, the skin quality was better with imiquimod treatment (RR 0.19, 95% CI 0.08 to 0.47, NNT = 1.5; Analysis 44.3).
To summarise, cryotherapy and 5% imiquimod had similar efficacy, but imiquimod had significantly better cosmetic outcome.
Comparisons with photodynamic treatments
Cryotherapy versus 5‐aminolaevulinic acid (ALA)‐ photodynamic therapy (PDT)
This intervention was addressed by one open study (Hauschild 2009b) comparing cryotherapy with photodynamic therapy (PDT) using red light and auto‐adhesive ALA patches. Both interventions treated participant individual lesions on the head once, and no prior lesion preparation was performed. Assessment was performed 12 weeks after the end of treatment. There was possible performance, detection, attrition, and reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 255 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts |
| ‐ | x | ‐ | ‐ |
Analysis of participant complete clearance clearly favoured the ALA‐PDT treatment over cryotherapy (RR 0.76, 95% CI 0.61 to 0.96, NNT = 7.2; Analysis 46.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 297 participants) | Skin irritation (N = 297 participants) | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x (none lost) | x | Qualitative | ‐ |
There were no participant withdrawals due to adverse events.
Significantly more participants treated with ALA‐PDT experienced skin irritation during (RR 0.63, 95% CI 0.54 to 0.74, NNT = 3.2) and 1 day after (RR 0.27, 95% CI 0.16 to 0.46, NNT = 3.7) treatment compared to cryotherapy (Analysis 46.2).
The minor adverse events reported in the cryotherapy group were eyelid oedema and swollen face, whereas pyoderma and emotional distress were documented for ALA‐PDT group. Headaches were reported in both groups.
In summary, in this single study, ALA‐PDT treatment was superior to cryotherapy for efficacy outcomes, but more skin irritation was associated with ALA‐PDT.
Cryotherapy versus methyl aminolevulinate (MAL)‐photodynamic therapy (PDT)
This intervention was addressed by 4 studies (Freeman 2003; Kaufmann 2008; Morton 2006; Szeimies 2002) comparing cryotherapy and PDT with 16% MAL for the treatment of actinic keratoses. All studies were open and used red light PDT. Characteristics of the studies are presented in the following table. There was possible performance, detection, and reporting bias for all studies, attrition bias for all studies except Morton 2006, and other bias for Freeman 2003 and Kaufmann 2008.
| Characteristic | ||||
| Study design | Parallel | Parallel | Intraindividual | Intraindividual |
| Anatomical locations | Face, scalp, others (< 10%) | Face or scalp | Face and scalp | Upper and lower extremities (98%), trunk, neck |
| Prior preparation of lesions (scale and crust removal) | Cryotherapy: yes PDT: yes | Cryotherapy: no PDT: yes | PDT: yes | PDT: yes (except mild lesions = 12%) |
| Number of treatment cycle | 1 (face and scalp) or 2 (other locations) | Cryotherapy : 1 PDT: 2 | 1 or 2 | 1 or 2 |
| Number of weeks between treatments | 1 | 1 | 12 | 12 |
| Number of freeze‐thaw cycles per treatment | 2 | 1 | 2 | 2 |
| Total freezing time (sec) | 24 + 18 | 12 to 26 | 16 | 20 + 14 |
| Individual lesion or field‐directed treatment (MAL) | Individual lesions | Individual lesions | Individual lesions | Individual lesions |
| Occlusion time with 16% MAL (hour) | 3 | 3 | 3 | 3 |
| PDT intensity (mW/cm²) | 70 to 200 | 50 to 250 | N/A | N/A |
| PDT dose (J/cm²) | 75 | 75 | 37 | 37 |
| Type of light source | Non‐coherent light | (CureLIght) | LED (Aktilite CL 128 lamp) | LED (Aktilite CL 128 lamp) |
| Time of assessment | 12 weeks after the end of treatment | 12 weeks after the end of treatment | 12 weeks after the end of treatment | 12 weeks after the end of treatment |
Primary outcomes
Most of the studies presented 'lesion complete response' as an efficacy outcome, which was not included in this review.
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 240 participants) |
| ‐ | ‐ | ‐ | ‐ | |
| ‐ | ‐ | ‐ | ‐ | |
| ‐ | ‐ | ‐ | Percentages | |
| ‐ | ‐ | ‐ | Percentages |
Morton 2006 and Kaufmann 2008 presented the percentages without the associated standard deviations. Thus, no statistical analysis could be performed. Based on these percentages presented in Analysis 45.1 and the data presented in the overview tables for cryotherapy and photodynamic therapy, the two treatments seem to have similar efficacy.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 619 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (see table below) |
| x | ‐ | ‐ | x | |
| x | ‐ | Only for MAL‐PDT and not included in the analysis | x | |
| x | ‐ | Intraindividual study not included in meta‐analysis | x | |
| x | ‐ | Intraindividual study not included in meta‐analysis | x |
In the parallel‐group studies, there was no difference in the number of participants who withdrew because of adverse events (Analysis 45.2). In the intraindividual studies, 4 of 119 (Morton 2006) and 2 of 121 (Kaufmann 2008) participants withdrew because of adverse events and 1 of them was related to MAL‐PDT treatment.
Kaufmann 2008 mentioned that the types of adverse events observed were mainly photosensitivity reaction (43% of 121 participants) and cold exposure injury (62% of 121 participants) for the MAL‐PDT and cryotherapy groups, respectively. Similar qualitative observation was mentioned by Morton 2006 (N = 119).
The types of cosmetic outcomes reported by the four studies are summarised in the following table.
| Parameter | (N = 122 participants) | ( N = ? participants) | ||
| Evaluation by investigator | X | X | X | X |
| Evaluation by participant | X | X | N/A | N/A |
| Outcome | 1) excellent or good 2) fair or poor | Excellent | 1) excellent 2) good 3) fair 4) poor | 1) excellent 2) good 3) fair 4) poor |
| Reported per participant | X (only for participants with > 75% reduction of total lesions) | X (only for participants with 100% reduction of total lesions) | N/A | N/A |
| Reported per lesion | N/A | X | X | X |
Because participants or right/left sides were randomised and not the lesions, only the data reported by participants were analysed. Freeman 2003 reported the percentages of completely cleared participants with excellent cosmetic outcome, but the number of participants completely cleared was not specified and the standard deviations associated with the percentages were not provided. Thus, no statistical analysis could be performed on these data. Similar percentages were obtained for investigator and participant assessments for MAL‐PDT (83% vs 76%) and cryotherapy (51% vs 56%). The authors reported significant differences between MAL‐PDT and cryotherapy groups. The investigator (RR 0.84, 95% CI 0.74 to 0.95, NNT = 6.5; Analysis 45.3) and participant (RR 0.93, 95% CI 0.86 to 1.01, NNT = 14.6; Analysis 45.4) evaluations in the Szeimies 2002 study also supported a better cosmetic outcome in the MAL‐PDT group.
To summarise, because most of the efficacy outcomes reported could not be included in our analyses, it is difficult to determine the relative efficacy of MAL‐PDT and cryotherapy. Data from one study suggested equivalence between the two treatments. MAL‐PDT treatment seems to result in better cosmetic outcomes than cryotherapy.
Photodynamic therapy
Photodynamic therapy employs light sources and photosensitising agents that may differ between studies. As this is a relatively new treatment method, testing different combinations of variables is necessary to attempt to identify the optimal PDT treatment form and regimen. Light sources vary from polychromatic to pulsed laser. Photosensitising agents aminolevulinic acid (ALA) and newer methyl‐aminolevulinic acid (MAL) were both used, depending on the study. Thus, results are presented in two sections: photodynamic therapy with ALA and photodynamic therapy with MAL. Within these sections, the results are presented in the following order: 1) comparisons between ALA or MAL and placebo, 2) comparisons with different photodynamic therapy variables, and 3) comparisons with other treatments. Photodynamic therapy could be used to treat individual lesions or a field.
Photodynamic therapy (PDT) with 5‐aminolaevulinic acid (ALA)
ALA‐PDT versus placebo‐PDT
This intervention was addressed by five studies (Hauschild 2009a; Hauschild 2009b; Jeffes 2001; Piacquadio 2004; Szeimies 2010b) investigating the use of aminolevulinic acid (ALA) and photodynamic therapy (PDT) compared to placebo‐PDT to treat actinic keratoses. Characteristics of the studies are presented in the following table. There was possible performance (Hauschild 2009b; Jeffes 2001; Piacquadio 2004), detection (Hauschild 2009b; Piacquadio 2004), attrition (Hauschild 2009b; Piacquadio 2004), reporting (Hauschild 2009a; Hauschild 2009b; Piacquadio 2004), and other (Piacquadio 2004) bias.
| Blue light | Red light | |||
| Characteristic | and | |||
| Study design | Assessor‐blinded intraindividual | Assessor‐blinded parallel | Double‐blinded parallel | Double‐blinded parallel |
| Anatomical locations | Face and scalp | Face or scalp | Head | Face, bald scalp, or both |
| Prior preparation of lesions (e.g. scale and crust removal) | N/A | N/A | No | Yes |
| Number of treatment cycle | 1 or 2 | 1 or 2 | 1 | 1 or 2 |
| Number of weeks between treatments | 8 | 8 | N/A | 12 |
| Individual lesion or field‐directed treatment | Individual lesions | Individual lesions | Individual lesions | Individual lesions |
| ALA formulation | 20% cream | 20% cream | Patch containing 8 mg | BF‐200 gel |
| Occlusion time (hour) | 14 to 18 | 14 to 18 | 4 | 3 |
| PDT intensity (mW/cm²) | 3, 5, 10 | 10 | N/A | Aktilite: 50‐70 PhotoDyn 750: 196 |
| PDT dose (J/cm²) | 2, 5,10 | N/A | 37 | Aktilite: 37 PhotoDyn 750: 170 |
| Illumination time (seconds) | N/A | 1000 | N/A | Aktilite: N/A PhotoDyn 750: 900 |
| Type of light source | Non‐laser fluorescent (Dusa BLU‐417) | visible (Blu‐U) | LED (Aktilite CL 128 lamp or Omnilux) | LED (Aktilite CL 128 lamp) or incoherent (PhotoDyn 750) |
| Time of assessment | 8 weeks after the end of each treatment | 8 weeks after the end of each treatment | 12 weeks after the end of each treatment | 12 weeks after the end of each treatment |
Subgroup analyses were performed to compare blue and red light photodynamic therapies. In addition, one study (Piacquadio 2004) provided efficacy data for individual anatomical locations, i.e. face or scalp, allowing additional subgroup analysis for blue light ALA or placebo with photodynamic treatment.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 701 participants) | Participant partial (> 75%) clearance (N = 243 participants) | Mean (changes) reduction in lesion counts |
| ‐ | intraindividual and not included in meta‐analysis | ‐ | ‐ | |
| ‐ | x | x | ‐ | |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | ‐ | ‐ |
Most of the studies gave a second treatment to uncured lesions after the first treatment, and they provided efficacy outcomes 8 to 12 weeks after the first treatment (1 treatment) and after 4 to 12 weeks after the last treatment (1 or 2 treatments). Thus, separate comparisons were performed for the number of treatments received.
In Jeffes 2001, lesions treated with ALA were completely cleared in 45.7% (16/35) of the participants after 1 treatment using blue light PDT, whereas lesions treated with placebo were completely cleared in only 5.7% (2/35). Similarly, the number of participants with complete clearance was significantly higher in the ALA‐PDT group than placebo‐PDT group for both blue and red light after one treatment (Analysis 47.1). The amplitude of the effect was similar between blue (RR 6.22, 95% CI 2.88 to 13.43, NNT = 2.0; Analysis 47.1) and red light (RR 5.94, 95% CI 3.35 to 10.54, NNT = 2.0; Analysis 47.1), but a larger increase in the RR associated with blue light treatment following an additional treatment on uncured lesions was observed (blue light: RR 9.33, 95% CI 3.59 to 24.26, NNT = 1.8; and red light: RR 6.20, 95% CI 2.40 to 15.99, NNT = 2.0; Analysis 47.2). This difference might be explained by the fact that only one study with red light performed a second treatment: Szeimies 2010b used two light sources to reflect more medical practices. A lower efficacy was obtained with the ALA/PhotoDyn 750 lamp (26/49 = 53%) than with ALA/Aktilite CL 128 (27/31 = 87%). The PhotoDyn lamp was used in 60% of the ALA and placebo participants, resulting in lower efficacy than the other 2 studies using only the Aktilite lamp after the first treatment.
Similar results were obtained with participant partial clearance for blue light ALA‐PDT with a RR of 4.38, 95% CI 2.47 to 7.79, NNT = 1.8 for 1 treatment (Analysis 47.4) and a RR of 6.51, 95% CI 3.22 to 13.15, NNT = 1.6 for 1 or 2 treatments (Analysis 47.5). There was no difference in the RRs for participants completely (Analysis 47.3) or partially (Analysis 47.6) cleared of lesions on the face or scalp. For both outcomes and both sites, ALA‐PDT was significantly better than placebo‐PDT.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 701 participants) | Skin irritation (N = 300 participants) | Minor adverse events excluding skin irritation (N = 543 participants) | Cosmetic outcome (see table below) |
| x (none lost) | ‐ | ‐ | x | |
| x (none lost) | ‐ | x | x | |
| x (none lost) | x | x | x | |
| x (none lost) | ‐ | Intraindividual study not included in meta‐analysis | x |
There were no participant withdrawals due to adverse events.
The number of participants experiencing skin irritation was significantly higher in the ALA‐PDT group compared to placebo‐PDT during illumination (RR 8.94, 95% CI 4.62 to 17.31, NNT = 1.3; Analysis 47.7) and after the treatment (RR 59.72, 95% CI 3.75 to 952.48, NNT = not applicable; Analysis 47.7).
None of the adverse events reported for blue light photodynamic therapy [injury (Analysis 47.8), hypertension (Analysis 47.9), skin hypertrophy (Analysis 47.11) and headache (Analysis 47.12)] were significantly different between the two treatments. For red light photodynamic therapy, Hauschild 2009a and Hauschild 2009b reported skin discolouration in one participant in the ALA group, which was not significantly different between ALA and placebo‐treated participants (Analysis 47.10).
The types of cosmetic outcomes reported by the five studies are summarised in the following table.
| Parameter | (N = 114 participants) | |||
| Evaluation by investigator | x (not specified) | x | x | x |
| Evaluation by participant | N/A | N/A | x | N/A |
| Outcome | Changes in pigmentation | Changes in pigmentation | 1) excellent 2) good 3) fair 4) poor | General outcome: 1) very good or good 2) unsatisfactory/impaired outcome Skin quality (qualitative) |
| Reported per participant | N/A | N/A | N/A | x |
| Reported per lesion | x | x | x (cleared lesions only) | N/A |
Cosmetic outcomes were reported by all studies, but only Szeimies 2010b reported its outcome per participant. The cosmetic outcomes assessed by the investigator were very good or good in 49% of ALA‐PDT and 27% in placebo‐PDT groups, which was significantly different (RR 1.83, 95% CI 1.03 to 3.25, NNT = 4.5; Analysis 47.13).
To summarise, ALA‐PDT was more effective than placebo‐PDT, and the efficacy is similar for blue or red light photodynamic therapy. For red light photodynamic therapy, using Aktilite CL 128 lamp gave better results than PhotoDyn 750 lamp. ALA treatment was generally associated with more skin irritation than placebo; however, ALA‐PDT resulted in better cosmetic outcomes.
ALA‐PDT: comparison between types of light source
This intervention was addressed by one study (Smith 2003) investigating ALA with one hour incubation followed by illumination with blue light or pulsed dye laser (PDL) for field‐directed treatment on the face or scalp, twice with a month interval. Assessment was performed at four weeks after the end of treatment. There was possible performance, detection, and reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 24 participants) | Participant partial (> 75%) clearance (N = 24 participants) | Mean (changes) reduction in lesion counts |
| ‐ | x | x | ‐ |
More participants receiving ALA‐blue light PDT compared to ALA‐PDL had complete (6/12 compared to 1/12) (Analysis 48.1) or partial (>75%) (9/12 compared to 5/12) (Analysis 48.2) clearance, respectively; however, this was not statistically significant.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 24 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (N = 24 participants) |
| x (none lost) | ‐ | ‐ | x |
There were no participant withdrawals due to adverse events.
None of the three cosmetic outcomes reported, i.e. improvements in global response, tactile roughness, and mottled hyperpigmentation, were significantly different between the two light sources (Analysis 48.3; Analysis 48.4; Analysis 48.5).
To summarise, insufficient data were provided to determine the superiority of one source of light over the other for field‐directed treatment of actinic keratoses with ALA‐PDT.
ALA‐PDT: comparison for different incubation times with ALA
This intervention was addressed by 1 study (Hauschild 2009c) comparing the efficacy of self‐adhesive ALA patch treating individual lesions for different incubation times (0.5, 1, 2, and 4 hours) before PDT (red light) treatment to treat actinic keratoses on the head and face. Assessments were performed at 4 and 8 weeks after the end of treatment. There was possible attrition and reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 140 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts |
| ‐ | x | ‐ | ‐ |
Efficacy was assessed at four (Analysis 49.1) and eight weeks (Analysis 49.2), and participant complete clearance was analysed for subgroups of the different combinations between shorter and longer incubation times. At 4 weeks, analyses of participant complete clearance did not favour shorter or longer times except for comparison between the shortest (0.5 hours) and the longest (4 hours), which favoured the longest incubation time (RR 0.50, 95% CI 0.26 to 0.95, NNT = 3.8). In contrast, all comparisons favoured the longer incubation times with the exception of 1 hour versus 2 hours at week 8 (Analysis 49.2). Thus, a longer incubation with ALA gave better long‐term results.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 149 participants) | Skin irritation | Minor adverse events excluding skin irritation (N = 149 participants) | Cosmetic outcome |
| x (maybe) | ‐ | x | ‐ |
Of 149 participants, 9 were not included in the final efficacy analysis and 3 of them terminated the study prematurely; however, the authors did not give more details about the reasons or associated treatments.
Five of 149 participants experienced adverse events related to treatment, which were 3 headaches (1 in each of the 0.5‐, 2‐, and 4‐hour groups), 1 nose bleed (in the 4‐hour group), and a mild increase in alanine transaminase (1 in the 0.5‐hour group). None of these adverse events were significantly associated with the incubation time (mild increase in alanine transaminase: Analysis 49.3; headache: Analysis 49.4; and nose bleed: Analysis 49.5). Other adverse events were reported but not in relation to the incubation groups.
To summarise, longer incubation with ALA resulted in an increase in long‐term efficacy.
ALA‐PDT versus 5‐fluorouracil
This intervention was addressed by 1 study (Smith 2003) comparing ALA‐PDT field‐directed treatment (twice with a 1‐month interval) using 2 different types of light sources (blue light and pulse dye laser) with 0.5% fluorouracil applied once or twice daily for 4 weeks on the face or scalp (field‐directed treatment). Assessment was performed four weeks after the end of treatment. There was possible performance, detection, and reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 36 participants) | Participant partial (> 75%) clearance (N = 36 participants) | Mean (changes) reduction in lesion counts |
| ‐ | x | x | ‐ |
Analyses of participant complete (Analysis 50.1) and partial (> 75%) (Analysis 50.2) clearance showed that the PDT treatments with blue light and the pulse dye laser (PDL) were comparable to 5‐fluorouracil. However, a tendency to favour 5‐fluorouracil over ALA‐PDT with pulsed dye laser could be observed for both outcomes (complete: RR 0.17, 95% CI 0.02 to 1.18; partial: RR 0.56, 95% CI 0.26 to 1.17), but this was not statistically significant.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 36 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (N = 36 participants) |
| x | ‐ | ‐ | x |
One of 12 participants in the 5‐fluorouracil group withdrew because of adverse events compared to none of the 24 participants in the ALA‐PDT groups, which was not significantly different (Analysis 50.3).
None of the 3 cosmetic outcomes reported improvements in global response (RR 0.74, 95% CI 0.44 to 1.25; Analysis 50.4). Tactile roughness (RR 0.92, 95% CI 0.52 to 1.61; Analysis 50.5) and mottled hyperpigmentation (RR 0.65, 95% CI 0.34 to 1.26; Analysis 50.6) were significantly different between 5‐fluorouracil and ALA‐PDT administered with the 2 light sources, but there was a general tendency to favour 5‐fluorouracil treatment. However, this was not statistically significant.
To summarise, no statistical difference could be observed between 5‐fluorouracil treatments and ALA with photodynamic therapy because of the small sample of this study. However, 5‐fluorouracil treatment had a tendency to result in better outcomes.
ALA‐PDT and imiquimod
This intervention was addressed by 1 intraindividual study (Sotiriou 2009) comparing 2 treatments of ALA‐red light PDT performed at a 15‐day interval on individual lesions and a dosing cycle of 5% imiquimod once per day 3 times per week for 4 weeks on, 4 weeks off, repeated if needed on the dorsal side of the hands and forearms (field‐directed treatment). Assessments were performed 4 and 24 weeks after the end of treatment. There was possible performance and detection bias.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts |
| ‐ | ‐ | ‐ | ‐ |
The study by Sotiriou 2009 reported "lesion complete response" as an efficacy outcome, which was not one of our primary outcomes.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 30 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome (N = 30 participants) |
| X (none lost) | ‐ | ‐ | x |
There were no participant withdrawals due to adverse events.
The authors of the Sotiriou 2009 study reported no significant difference in the investigator‐assessed excellent cosmetic outcome for lesions in the two treatment groups.
To summarise, the efficacy of ALA‐PDT and imiquimod could not be compared.
ALA‐PDT versus cryotherapy
This comparison was discussed in the cryotherapy section above, and the results presented in Table 3 correspond to Analysis 51.1 and Analysis 51.2 .
Photodynamic therapy (PDT) with methyl‐aminolevulinic (MAL)
MAL‐PDT versus placebo‐PDT
This intervention was addressed by seven studies (Dragieva 2004a; Freeman 2003; Pariser 2003; Pariser 2008; Photocure‐Australian 2004; Photocure‐US 2004; Szeimies 2009) investigating the use of methyl‐aminolevulinic (MAL) and photodynamic therapy (PDT) compared to placebo‐PDT to treat actinic keratoses. The Dragieva 2004a study was performed with immunocompromised participants (organ transplants recipients). Characteristics of the studies are presented in the following table. There was possible performance (Dragieva 2004a; Freeman 2003), detection (Dragieva 2004a; Freeman 2003), attrition (Freeman 2003; Pariser 2003; Photocure‐Australian 2004; Photocure‐US 2004), reporting (Freeman 2003; Pariser 2003; Photocure‐Australian 2004; Photocure‐US 2004), and other (Freeman 2003) biases.
| Red light | ||||||
| Characteristic | ||||||
| Study design | Double‐blinded parallel | Double‐blinded parallel | Double‐blinded intraindividual | Double‐blinded parallel | Double‐blinded parallel | Double‐blinded parallel |
| Anatomical locations | Face or scalp | Face and scalp | Face or scalp, neck, extremities | Face and scalp | Face and scalp | Face and scalp, hand (< 1%) |
| Prior preparation of lesions (e.g. scale and crust removal) | Yes | Yes | Yes | Yes | Yes | Yes |
| Number of treatment cycle | 2 | 2 | 2 | 2 | 2 | 2 |
| Number of weeks between treatments | 1 | 1 | 1 | 1 | 1 | 1 |
| Individual lesion or field‐directed treatment | Individual lesions | Individual lesions | Field‐directed treatment | Individual lesions | Individual lesions | Individual lesions |
| MAL formulation | 16% cream | 16% cream | N/A | 16.8% cream | 16.8% cream | 16% cream |
| Occlusion time (hour) | 3 | 3 | 3 | 2.5 to 4 | 3 | 3 |
| PDT intensity (mW/cm²) | 50 to 250 | 50 to 200 | 80 | N/A | N/A | 56 to 83 |
| PDT dose (J/cm²) | 75 | 75 | 75 | 75 | 37 | 37 |
| Illumination time (seconds) | 600 | 480 | N/A | N/A | 480 | 540 |
| Type of light source | Broadband (CureLight) | Broadband non‐coherent light | Broadband non‐coherent (Waldmann PDT 1200) | Broadband (CureLight) | Light‐emitting diode (LED) (Aktilite CL 128) | Light‐emitting diode (LED) (Aktilite CL 128) |
| Time of assessment | 12 weeks after the end of treatment | 12 weeks after the end of treatment | 16 weeks after the end of treatment | 12 weeks after the end of treatment | 12 weeks after the end of treatment | 12 weeks after the end of treatment |
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 499 participants) | Participant partial (> 75%) clearance (N = 191 participants) | Mean (changes) reduction in lesion counts |
| ‐ | ‐ | ‐ | ‐ | |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | x | ‐ | |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | ‐ | ‐ |
Freeman 2003 reported only lesion complete response, which is not included in this review.
In immunocompetent participants, pooled RR for participant complete clearance favoured MAL/red light PDT (RR 4.46, 95% CI 3.17 to 6.28, NNT = 1.9; Analysis 52.1). Similarly, pooled RR (Photocure‐Australian 2004; Photocure‐US 2004) for participant partial (> 75%) clearance also favoured MAL‐PDT over placebo‐PDT (RR 3.28, 95% CI 1.73 to 6.23, NNT = 1.8; Analysis 52.2). In immunosuppressed participants, 13 out of 17 participants were completely cleared on the MAL‐PDT‐treated side and none on the placebo‐PDT‐treated side, supporting the superiority of MAL photodynamic therapy in these organ transplants patients.
No publication bias was detected for the studies with immunocompetent participants based on the funnel plot (Figure 4).
Funnel plot of comparison: 50 MAL‐PDT (red light) versus placebo‐PDT (red light), outcome: 50.1 Participant complete clearance.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 402 participants) | Skin irritation | Minor adverse events excluding skin irritation (N = 115 participants) | Cosmetic outcome (see text below) |
| x | ‐ | ‐ | x | |
| x | ‐ | ‐ | x | |
| ‐ | ‐ | ‐ | ‐ | |
| ‐ | ‐ | ‐ | x | |
| x (none lost) | ‐ | ‐ | ‐ | |
| x (none lost) | ‐ | x | ‐ |
The pooled risk ratio for two of the studies showed no significant difference in the number of participants who withdrew because of adverse events between MAL‐PDT‐ and placebo‐PDT‐treated groups (Analysis 52.3). In addition, two other studies had no withdrawals due to adverse events in both treatment groups. These data together suggest that there is no difference between the two groups.
Szeimies 2009 reported one event of headache (one participant; Analysis 52.4) and three events of eyelid oedema in the MAL‐PDT group.
Excellent cosmetic outcomes were observed for MAL‐PDT in 81% to 93% of participants completely cleared [Freeman 2003 (N = the number of participants evaluated was not given); Pariser 2003 (N = 32)], but in the absence of data reported for placebo‐PDT, these values could not be compared. No significant difference was observed for hyperpigmentation (N = 191; Analysis 52.5).
To summarise, MAL‐PDT was clearly more efficient than placebo‐PDT to treat actinic keratoses.
MAL‐PDT: comparisons between types of light source
This intervention was addressed by two studies (von Felbert 2010; Wiegell 2008). Wiegell 2008 compared field‐directed treatment using MAL‐PDT with light‐emitting diode (LED) red light and field‐directed treatment using MAL‐PDT with daylight (sun) on the face or scalp (field‐directed treatment). After removal of crust and hyperkeratoses, MAL cream was applied for three hours. After 30 minutes occlusion, the daylight‐treated side was exposed to outside daylight for 2.5 hours, and then the red light side, which stayed under occlusion for 3 hours, was treated with a LED lamp. von Felbert 2010 compared individual lesion treatment (one or two treatments) using MAL‐PDT with red light LED or a broadband visible plus water‐filtered infrared A on the face or scalp. Each treatment group was further separated into two subgroups: with and without cooling spray during illumination. Assessments were performed at 12 (von Felbert 2010; Wiegell 2008), 24 (von Felbert 2010), and 48 weeks (von Felbert 2010). There was possible performance (Wiegell 2008) and attrition (von Felbert 2010) bias.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 80 participants) | Participant partial (> 75%) clearance (N = 80 participants) | Mean (changes) reduction in lesion counts (N = 30 participants) |
| ‐ | ‐ | ‐ | Absolute values and percentages | |
| ‐ | x | x | ‐ |
No difference in the mean reduction in lesion counts was found between red (8.0 + 5.6, mean + SD, 71%) and daylight (8.4 + 5.4, 79%) (Analysis 54.1).
At 12 months, the number of participants with complete (RR 1.50, 95% CI 0.90 to 2.51; Analysis 53.1) clearance had a tendency to be higher in the MAL‐PDT using red light LED as the illumination source, although this was not statistically significant, compared to broadband visible plus water‐filtered infrared A. In contrast, no tendency could be observed for partial clearance (RR 1.03, 95% CI 0.85 to 1.25; Analysis 53.2).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 110 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x (none lost) | ‐ | ‐ | ‐ | |
| x (none lost) | ‐ | ‐ | ‐ |
There were no participant withdrawals due to adverse events.
It is worth noting that the authors of the Wiegell 2008 study reported a pain score significantly lower during daylight exposure than red light exposure. The adverse events were more severe in the sun‐exposed side for 42% of the participants and more severe in the red light side for 21% following treatment (Wiegell 2008).
To summarise, performing MAL‐PDT with daylight exposure resulted in similar efficacy to MAL‐PDT with red light treatment. However, a tendency for better results with red light LED compared to broad visible light with water filtered infrared A was observed.
MAL‐PDT: comparison for different incubation times with MAL
This intervention was addressed by 1 study (Wiegell 2011a) comparing the efficacy of field‐directed treatment MAL‐PDT for different illumination times with daylight in the presence of 16% MAL cream. Sunscreen was applied for 15 minutes to the treatment area on the face and scalp, and crusts and scales were gently removed before MAL application. After 30 minutes occlusion with MAL, participants were exposed to the sun for 1.5 or 2.5 hours, resulting in exposure to MAL for 2 and 3 hours. All lesions present in the area were treated, but only grade 1 lesions were included in the data analysis by the authors of the study. Assessment was performed 12 weeks after the end of treatment. There was possible performance bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 120 participants) |
| ‐ | ‐ | ‐ | Absolute values and percentages |
No difference was found between 2 and 3 hours MAL incubation with daylight PDT for mean reduction of lesion counts (MD 0.10, 95% CI ‐3.17 to 3.37; Analysis 55.1) or mean percentage reduction in lesion counts (MD 2.60, 95% CI ‐6.46 to 11.66; Analysis 55.2). The latter had a tendency to favour the shortest incubation time, but this was not statistically significant.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 120 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x (none lost) | ‐ | ‐ | ‐ |
There were no participant withdrawals due to adverse events.
To summarise, similar efficacy was obtained for 2‐ or 3‐hour incubation with 16% MAL with sun exposure for 1.5 and 2.5 hours, respectively.
MAL‐PDT: comparison for different concentrations of MAL
This intervention was addressed by 1 intraindividual study (Wiegell 2009) comparing the efficacy of field‐directed treatment with MAL‐PDT for different MAL concentrations (16% versus 8%) with daylight PDT for actinic keratoses on the face or scalp. Sunscreen was applied for 15 minutes to the treatment area, and crusts and scales were gently removed before MAL application. The participants were then instructed to spend as much time as possible outside for the rest of the day and wash off the cream at bedtime. The light dose was measured by a dosimeter. Assessment was performed 12 weeks after the end of treatment. There was possible reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 29 participants) |
| ‐ | ‐ | ‐ | Absolute values and percentages |
Similar efficacy was obtained for the 2 concentrations of MAL, i.e. mean reduction in lesion counts of 14.8 + 8.2 (mean + SD, 76.9%) for 16% MAL and 14.5 + 7.6 (79.5%) for 8% MAL (Analysis 56.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 30 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | ‐ | ‐ | ‐ |
One of 30 participants withdrew because of unrelated adverse events (terminal illness).
To summarise, 8% and 16% MAL treatments gave similar results with daylight photodynamic therapy to treat actinic keratoses.
MAL‐PDT: comparison between single and multiple MAL‐PDT treatment
This intervention was addressed by one study (Tarstedt 2005) comparing the efficacy of one MAL‐PDT treatment with red light and three‐hour incubation compared to the efficacy of multiple MAL‐PDT treatments, which involved two treatment sessions one week apart, on individual lesions on the face and scalp. Lesions not cleared after 12 weeks were retreated. Assessment was performed 12 weeks after the end of each cycle of treatment. There was possible performance, detection, and attrition bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 211 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts |
| ‐ | x | ‐ | ‐ |
The number of participants achieving complete clearance was significantly higher in the single MAL‐PDT treatment group compared to the multiple MAL‐PDT treatment (RR 1.17, 95% CI 1.03 to 1.33; Analysis 57.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 211 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x | ‐ | ‐ | Per lesion (not included in analysis) |
The number of participants who withdrew because of adverse events was not significantly different between single MAL‐PDT and multiple MAL‐PDT (Analysis 57.2).
To summarise, multiple MAL‐PDT treatments were associated with more adverse events and were less efficacious than a single treatment.
MAL‐PDT versus cryotherapy
This comparison was discussed in the cryotherapy section above and the results presented in Table 3 correspond to Analysis 45.1 and Analysis 58.1.
ALA‐PDT versus MAL‐PDT
This intervention was addressed by 1 intraindividual study (Moloney 2007) comparing 20% ALA incubated for 5 hours and 20% MAL incubated for 3 hours before PDT under identical conditions for field‐directed treatment of extensive actinic keratoses on the scalp. Assessment was performed four weeks after the end of treatment. There was possible reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 16 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 15 participants) |
| ‐ | Field complete clearance | ‐ | Absolute values |
Because of the intraindividual design of the Moloney 2007 study, participant complete clearance could not be included in meta‐analysis, but there was no significant difference between the effectiveness of the 2 treatments in curing actinic keratosis lesions based on participant complete clearance (ALA: 6/16 and MAL: 7/16) and mean reduction in lesion counts (Analysis 59.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 16 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x (none lost) | ‐ | ‐ | ‐ |
There were no participant withdrawals due to adverse events.
To summarise, there was no significant difference between the effectiveness of MAL and ALA treatments to treat extensive actinic keratoses.
MAL‐PDT versus 5‐fluorouracil
This intervention was addressed by 1 intraindividual study (Perrett 2007) comparing 3‐hour incubation with MAL followed by red light PDT with 5% 5‐fluorouracil twice daily for 3 weeks for treatment of individual actinic keratosis lesions and carcinoma in situ on the forearms and hands of organ transplant participants (immunosuppressed). Assessments were performed at 4, 12, and 24 weeks after the end of treatment. Data for efficacy but not safety outcomes were available separately for actinic keratoses. There was possible performance and detection bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 4 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts |
| ‐ | x | ‐ | ‐ |
Because of the intraindividual design of the study, the data for the participant complete clearance could not be included in a meta‐analysis. Thus, the efficacy results at one, three, and six months after treatments are presented in the following table.
| Assessment at (months) | MAL‐PDT | 5‐fluorouracil |
| 1 | 4/4 | 0/4 |
| 3 | 4/4 | 1/4 |
| 6 | 4/4 | 1/4 |
Based on this small sample size study, MAL‐PDT seemed to be more effective at treating actinic keratoses in organ transplant participants than 5‐fluorouracil under the conditions used.
Secondary outcomes
Because of the pooled data for carcinoma in situ and actinic keratoses, none of our secondary outcomes could be taken from the study by Perrett 2007.
To summarise, despite the small sample size used in Perrett 2007, efficacy data suggested that MAL‐PDT was more efficacious than 5‐fluorouracil to treat actinic keratoses in immunosuppressed participants
Trichloroacetic acid peel
Trichloroacetic acid peel versus 5‐fluorouracil
This intervention was addressed by 1 study (Hantash 2006) comparing trichloroacetic acid peel with 5% 5‐fluorouracil applied twice daily for 3 weeks on the face. Assessment was performed 12 weeks after the end of treatment. There was possible performance and detection bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 18 participants) |
| ‐ | ‐ | ‐ | Percentages |
Analysis of mean percentage of reduction in lesion counts did not significantly favour any treatment, but there was a tendency to favour the chemical peel (MD 5.80, 95% CI ‐3.78 to 15.38; Analysis 60.1).
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 19 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x (none lost) | ‐ | ‐ | ‐ |
There were no participant withdrawals due to adverse events.
To summarise, additional data are needed to confirm the superiority of the trichloroacetic acid chemical peel over 5‐fluorouracil to treat actinic keratoses.
Trichloroacetic acid peel versus carbon dioxide laser resurfacing
This comparison was presented in the laser resurfacing section above.
(5) Combinations of topical and oral treatments with mechanical or chemical interventions
Cryotherapy combined with betulin‐based oleogel
This intervention was addressed by one study (Huyke 2009) comparing cryotherapy with liquid nitrogen to cryotherapy combined with betulin‐based oleogel on the face, scalp, or other locations. Cryotherapy of participant lesions was performed once on lesions on the face and twice on lesions on the rest of the body, whereas betulin‐based oleogel was applied twice daily for an unspecified duration. Assessment was performed at three months after the beginning of the treatment. There was possible performance and detection bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 30 participants) | Participant partial (> 75%) clearance (N = 30 participants) | Mean (changes) reduction in lesion counts |
| ‐ | x | x | ‐ |
Additional treatment with betulin‐based oleogel did not significantly change participant complete (Analysis 61.1) or partial (> 75%) clearance rates (Analysis 61.2) obtained with cryotherapy.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 30 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x (none lost) | ‐ | ‐ | ‐ |
There were no participant withdrawals due to adverse events.
To summarise, the use of betulin‐based oleogel after cryotherapy did not improve the efficacy of the cryotherapy.
Cryotherapy combined with 5‐fluorouracil
This intervention was addressed by 2 studies (Jorizzo 2004; Jorizzo 2006) comparing 0.5% 5‐fluorouracil or placebo applied daily to lesions on the face, scalp, ears, neck, and lips for 7 days combined with cryotherapy at week 4 for uncured lesions for 1 (Jorizzo 2004) to 3 (Jorizzo 2006) cycles. Assessment was performed at 4 weeks after the end of treatment. There was possible reporting (Jorizzo 2006) and other (Jorizzo 2006) bias.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared | Participant complete clearance (N = 144 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 144 participants) |
| ‐ | x | ‐ | Absolute values and percentages | |
| ‐ | x | ‐ | Absolute values and percentages |
Pretreatment with 0.5% 5‐fluorouracil before cryotherapy for 1 (RR 4.08, 95% CI 1.63 to 10.23, NNT = 4.6) or 2 (RR 3.27, 95% CI 1.82 to 5.88, NNT = 2.8), but not for 3 cycles, resulted in higher participant complete clearance (Analysis 62.1) compared to placebo combined with cryotherapy.
The absolute mean reduction in lesion counts and their associated standard deviations were calculated from the mean lesion counts at baseline and the end of the 3 different treatment cycles. The standard deviation associated with the mean percentage of reduction in lesion counts was only reported for the first treatment cycle in Jorizzo 2004. Thus, statistical analysis of this outcome could not be performed. This difference in efficacy between 0.5% 5‐fluorouracil with cryotherapy and vehicle with cryotherapy was supported by the mean percentage of reduction in lesion counts presented in the following table and the significant mean difference for the first cycle (MD 21.40, 95% CI 5.10 to 37.70; Analysis 62.3), but not by the analysis of mean reduction of lesion counts (Analysis 62.2).
| Mean percentage of reduction in lesion counts | |||
| Study | Number of cycles | Vehicle + cryotherapy (mean + SD) | 5‐FU + cryotherapy (mean + SD) |
| 1 | 45.6% + 54.7% | 67% + 43.6% | |
| 2 | 57.8% | 86.3% | |
| 3 | 65.7% | 77.8% | |
The results presented in the additional Table 4 comparing vehicle with cryotherapy and 5‐FU with cryotherapy correspond to Analysis 63.1, Analysis 63.2, and Analysis 63.3.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 144 participants) | Skin irritation | Minor adverse events excluding skin irritation (N = 144 participants) | Cosmetic outcome |
| x (none lost) | ‐ | x (eye irritation) | ‐ | |
| x | ‐ | x (including Jorizzo 2004) | ‐ |
In the first treatment cycle of the Jorizzo 2004 and Jorizzo 2006 study, there were no participant withdrawals due to adverse events. Insufficient information was provided to determine how many participants were lost due to adverse events for the whole study.
None of the adverse events reported were significantly different between cryotherapy alone and cryotherapy combined with 5‐fluorouracil. In general, eye irritation (Analysis 62.10) and conjunctivitis (Analysis 62.9) were the most commonly‐reported adverse reactions for both groups and the same numbers of participants in each group experiencing it.
To summarise, the efficacy of cryotherapy could be increased with pretreatment with 0.5% 5‐fluorouracil if used for 1 or 2, but not 3, cycles.
Cryotherapy combined with imiquimod
This intervention was addressed by three studies (Jorizzo 2010; NCT00774787; Tan 2007). The studies compared cryotherapy followed by vehicle and cryotherapy followed with imiquimod treatment. In Jorizzo 2010, 4 to 14 lesions were treated with cryotherapy, and 5 lesions were left untreated before randomisation. The method used to select which lesions were treated with cryotherapy was not specified. Thus, the data from this study comparing cryotherapy with imiquimod and imiquimod alone could not be used in our analyses. NCT00774787 had an intraindividual study design, whereas all the other studies had a parallel‐group design. The anatomical locations, dosing regimens, and assessment time are presented in the following table. There was possible performance (NCT00774787), attrition (Tan 2007), reporting (Jorizzo 2010; NCT00774787; Tan 2007), and other (Tan 2007) biases.
| Study | Anatomical locations | Cryotherapy (followed or not with placebo) | Cryotherapy followed by imiquimod | Imiquimod alone | Time of assessment |
| Face or scalp | Once | 5% imiquimod 2 times/week for 8 weeks | No | 4 weeks after the end of treatment | |
| Face | Once | 3.75% imiquimod 3 times/week for 2 weeks on/2 weeks off/2 weeks on | 3.75 %imiquimod 3 times/week for 2 weeks on/ 2 weeks off/2 weeks on | 20 weeks after the end of treatment | |
| Face or bald scalp | Once | 5% imiquimod 3 times/week for 4 weeks | No | 4 to 8 weeks after the end of treatment |
Primary outcomes
| Study | Global improvement indices for completely improved or cleared | Participant complete clearance (N = 339 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 274 participants) |
| ‐ | x | ‐ | ‐ | |
| ‐ | x | ‐ | Percentages | |
| ‐ | Intraindividual study | ‐ | Percentages |
The primary outcomes were further divided into 3 outcomes: 1) for target lesions, i.e. cryotherapy‐treated lesions visible at baseline; 2) for subclinical lesions, i.e. lesions not visible at baseline but visible during the study; and 3) all lesions, i.e. target and subclinical lesions.
More participants had complete clearance on the cryotherapy combined with imiquimod side (8/27 = 30%) than the side that had cryotherapy alone (5/27 = 19%) in the intraindividual study. Cryotherapy combined with imiquimod had a tendency (but this was not statistically significant) to result in more participants with target lesions (cryotherapy‐treated: RR 0.62, 95% CI 0.36 to 1.04; Analysis 64.2) or subclinical lesions (RR 0.57, 95% CI 0.33 to 1.01; Analysis 64.3) completely cured compared to cryotherapy. By contrast, there was statistically significant complete clearance of all lesions in participants in Jorizzo 2010 (RR 0.20, 95% CI 0.05 to 0.73; Analysis 64.1); however, this could be due to the fact that the analysis in Jorizzo 2010 included the 5 lesions untreated with cryotherapy.
The combined cryotherapy with 3.75% imiquimod therapy was also significantly favoured compared with the cryotherapy‐only treated side for mean percentages of reduction for all lesions (MD ‐34.10, 95% CI ‐41.38, to ‐26.82; Analysis 64.4) but not when 5.0% imiquimod was used (MD ‐11.20, 95% CI ‐26.53 to 4.13; Analysis 64.4). The results from the 2 studies could not be pooled due to the high heterogeneity between the 2 studies (I² statistic = 86%). It is worth noting that the study favouring the combined therapy had a parallel design, whereas the study not favouring the combined therapy was an intraindividual study. Only the study with 3.75% imiquimod reported the mean percentage of reduction for target lesions only (MD ‐10.80, 95% CI ‐17.37 to ‐4.23; Analysis 64.5), which favoured the combined therapy.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 339 participants) | Skin irritation (N = 312 participants) | Minor adverse events excluding skin irritation (N = 312 participants) | Cosmetic outcome (N = 274 participants) |
| x | x | x | ‐ | |
| x | x | x (only for 2 groups: cryotherapy with placebo and cryotherapy with imiquimod) | x (only for 2 groups: cryotherapy with placebo and cryotherapy with imiquimod) | |
| x | ‐ | Pooled data not included | x |
In the intraindividual study, NCT00774787, there were no participant withdrawals due to adverse events. The pooled risk ratio for Tan 2007 and Jorizzo 2010 showed no difference between cryotherapy with vehicle and cryotherapy with imiquimod groups (RR 0.93, 95% CI 0.28 to 3.07; Analysis 64.6).
The number of participants experiencing skin irritation had a tendency to be higher in the group receiving additional treatment with imiquimod compared to cryotherapy alone (RR 0.39, 95% CI 0.10 to 1.54; Analysis 64.7).
The number of participants experiencing fatigue (RR 0.09, 95% CI 0.01 to 1.69; Analysis 64.8), nausea (RR 0.09, 95% CI 0.01 to 1.69; Analysis 64.9), and myalgia (RR 0.21, 95% CI 0.02 to 1.76; Analysis 64.10) tended to be higher with additional imiquimod treatment, whereas the 3 respiratory adverse events, upper respiratory tract infection (RR 1.34, 95% CI 0.51 to 3.48; Analysis 64.11), bronchitis (RR 5.21, 95% CI 0.62 to 43.92; Analysis 64.12), and sinusitis (RR 11.45, 95% CI 0.64 to 204.88; Analysis 64.13) tended to be higher in the cryotherapy alone group. None of the minor adverse events were statistically significant. One case of skin infection due to cryotherapy had been reported by Tan 2007, but the treatment group (i.e. placebo or imiquimod) was not specified.
Additional imiquimod treatment with cryotherapy significantly improved the cosmetic outcome compared to cryotherapy alone in all individual cosmetic outcomes reported by Jorizzo 2010 (fine lines, tactile roughness, mottled pigmentation, and sallowness) as well as global photoageing score (RR 0.37, 95% CI 0.25 to 0.56, NNT = 3.1; Analysis 64.15). Cosmetic outcome assessments by participant and investigator in NCT00774787 showed similar results for the additional use of imiquimod with cryotherapy. In this study, analysis of participant assessment favoured the additional use of imiquimod, whereas analysis of investigator assessment did not favour its use. This could be explained by the fact that no placebo was used in this study reporting this cosmetic outcome, making the participants unblinded to the treatment and maybe biased towards the additional treatment with imiquimod; in contrast, the assessor was blinded.
The results presented in the additional Table 5 for imiquimod comparisons correspond to Analysis 65.1, Analysis 65.2,Analysis 65.3, and Analysis 65.4.
To summarise, combination of cryotherapy and imiquimod treatments resulted in significantly better efficacy compared to the cryotherapy alone. Use of imiquimod cream after cryotherapy increased in general the number of participants experiencing adverse events, but resulted in significantly better cosmetic outcome.
ALA‐PDT combined with diclofenac in 2.5% hyaluronic acid gel pretreatment
This intervention was addressed by 1 study (Van der Geer 2009) investigating the efficacy of field‐directed treatment of ALA‐red light PDT on lesions on the dorsal side of the hands pretreated with diclofenac in 2.5% hyaluronic acid gel or 2.5% hyaluronic acid gel, twice daily for 4 weeks. Two weeks after diclofenac treatment, ALA was incubated for 4 hours then PDT with red light fractions at 80 J/cm² was performed for 16 minutes. Assessments were performed 6 weeks, and 6 and 12 months after the end of treatment. There was possible reporting bias associated with this study.
Primary outcomes
| Study | Global Improvement indices for completely improved or cleared (N = 9 participants) | Participant complete clearance | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 9 participants) |
| Mean scores | ‐ | ‐ | Absolute values |
The values provided for mean reduction in lesion counts at 6 weeks, 6 and 12 months (Analysis 66.2), and mean global improvement indices scores at 6 months (Analysis 66.1) were all lower in the vehicle group. The authors stated there was a significant difference in the mean number of lesions at 12 months (P = 0.017), but not in the mean reduction of lesion counts (P = 0.34) between the diclofenac and vehicle groups. However, it was impossible to test if these differences were statistically significant because measurement of variability, i.e. standard deviations or standard errors of the mean, were not provided.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 9 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| x (none lost) | ‐ | ‐ | ‐ |
There were no participant withdrawals due to adverse events.
To summarise, pretreatment with diclofenac in 2.5% hyaluronic acid gel did not increase the efficacy of ALA‐PDT treatment of actinic keratoses.
ALA‐PDT combined with imiquimod
This intervention was addressed by 1 intraindividual study (Shaffelburg 2009) investigating 2 ALA‐blue light PDT treatments with an interval of 4 weeks directed to a field of lesions.This was followed after another 4 weeks by 5% imiquimod or placebo applied once per day on the face (field‐directed treatment), on 2 days per week for 16 weeks [ALA‐blue light PDT followed with imiquimod versus ALA‐blue PDT followed with placebo]. Assessments were performed at baseline and months 1, 2, 3, 4, 6, and 12 of the study. There was possible reporting bias.
Primary outcomes
| Study | Global improvement indices for completely improved or cleared | Participant complete clearance (N = 25 participants) | Participant partial (> 75%) clearance | Mean (changes) reduction in lesion counts (N = 25 participants) |
| ‐ | x | ‐ | Absolute values and percentages |
The participant complete clearance was similar with (2/25) or without (2/25) additional imiquimod treatment after ALA‐PDT. The mean reduction in lesion counts was 19.9 (86.7%) for the imiquimod‐treated group and 16.0 (73.1%) for the placebo group. However, in the absence of standard deviations or standard errors of the mean values, no statistical analysis was possible to determine the significance of these data.
Secondary outcomes
| Study | Withdrawal due to adverse events (N = 25 participants) | Skin irritation | Minor adverse events excluding skin irritation | Cosmetic outcome |
| X (none lost) | ‐ | ‐ | ‐ |
There were no participant withdrawals due to adverse events.
To summarise, an additional treatment with imiquimod after ALA‐PDT did not improve the efficacy of the treatment for actinic keratosis.
Discussion
Summary of main results
Primary outcomes
Actinic keratoses remain unchanged, proliferate, regress, reappear, or develop into squamous cell carcinoma. Thus, comparison to a placebo control group gives a better estimate of the efficacy of an intervention for actinic keratoses. Significant estimate effects compared to vehicle or placebo were obtained for the following interventions.
1) For all reported efficacy outcomes: diclofenac (3/3 outcomes, number of studies (n) = 6, number of participants (N) = 723), 5‐fluorouracil (3/3 outcomes, n = 3, N = 528), ingenol mebutate (2/2 outcomes, n = 3, N = 540), sunscreen (1/1 outcome, n = 1, N = 588), ALA‐PDT (2/2 outcomes, n = 4, N = 814), and MAL‐PDT (2/2 outcomes, n = 5, N = 486).
2) For 50% or more of the reported efficacy outcomes: adapalene (1/2 outcomes, n = 1, N = 90), imiquimod (3/5 outcomes, n = 17, N = 3417), isotretinoin (1/2 outcomes, n = 1, N = 100), and masoprocol (1/2 outcomes, n = 1, N = 176).
3) For none of the reported efficacy outcomes: calcipotriol (vitamin D, 0/2 outcomes, n = 1, N = 9), DFMO (0/1 outcome, n = 1, N = 48), β‐1,3‐D‐glucan (0/1 outcome, n = 1, N = 20), nicotinamide (0/1 outcome, n = 1, N = 30), DL‐α‐tocopherol (vitamin E, 0/1 outcome, n = 1, N = 48), and etretinate (0/1 outcome, n = 1, N = 50).
Studies that compare the different concentrations of an intervention were included in our analysis. These studies were conducted for adapalene, colchicine, 5‐fluorouracil, imiquimod, ingenol mebutate, and MAL. Adalpene was the only intervention to demonstrate a difference in efficacy as a result of different concentrations.
The photosensitiser incubation time and light source were variables that were considered by several studies conducted on photodynamic therapy. One study comparing 0.5‐, 1‐, 2‐, and 4‐hour incubations with ALA showed that longer incubation before the photodynamic therapy resulted in better efficacy than a shorter incubation for 4 of the 6 possible comparisons between the different incubation times (see overview for photodynamic therapy in Table 3). In contrast, a similar efficacy was found for two‐ and three‐hour incubation with MAL before photodynamic therapy using daylight. No difference in efficacy was detected between the different light sources for photodynamic therapy (ALA: blue vs red light, blue light vs pulsed dye laser, and MAL: red light LED vs daylight, red light vs broadband visible plus water‐filtered infrared A).
We analysed interventions that investigated the efficacy of combined interventions, which generally combined field‐directed therapy with treatment for individual lesions. Pretreatment with 0.5% 5‐fluorouracil before cryotherapy and imiquimod after cryotherapy significantly improved the efficacy of cryotherapy (see overview for cryotherapy in Table 4). In contrast, no improvement in efficacy was detected when the following interventions were combined: additional tretinoin treatment to 5‐fluorouracil, additional betulin‐based oleogel to cryotherapy, pretreatment with diclofenac before ALA‐PDT, and imiquimod treatment after MAL‐PDT.
Several studies compared the efficacy of two different interventions. These interventions may be field‐directed treatments applied to a large area of clinical and subclinical lesions (topical creams, resurfacing, field‐directed photodynamic therapy, and chemical peel), or treatments that specifically target clinical lesions, (cryotherapy and individual lesion‐directed photodynamic therapy). Topical aretinoid methyl sulfone (Ro 14‐9706) was significantly more efficacious than topical tretinoin for only 1 of 2 outcomes reported by one study. Topical 5‐fluorouracil was more efficacious than topical masoprocol (2/3 outcomes, n = 1, N = 49) and cryotherapy (1/1 outcome, n = 1, N = 49), but had similar efficacy to topical imiquimod (2/2, n = 2, N = 89), carbon dioxide laser resurfacing (1/1 outcome, n = 1, N = 14), Er:YAG laser resurfacing (2/2 outcomes, n = 1, N = 55), ALA‐PDT for individual lesions (2/2 outcomes, n = 1, N = 36), and trichloroacetic acid peel (1/1 outcome, n = 1, N = 18) based on the data provided. However, more data are needed to be able to conclude on the difference in efficacy between 5‐fluorouracil and MAL‐PDT. Topical imiquimod efficacy was also similar to topical diclofenac (1/1 outcome, n = 1, N = 49) and cryotherapy (1/1 outcome, n = 1, N = 51) efficacies, but more data are needed to be able to compare imiquimod to ALA‐PDT for individual lesions. Betulin‐based oleogel and cryotherapy had similar efficacy (2/2 outcomes, n = 1, N = 28). Cryotherapy showed lower efficacy compared to ALA‐PDT for individual lesions (1/1 outcome, n = 1, N = 72), but more data are needed for the comparison with MAL‐PDT for individual lesions. However, field‐directed treatments with ALA‐PDT and MAL‐PDT had similar efficacy (2/2 outcomes, n = 1, N = 15). Based on these comparisons, these interventions could be ranked based on their relative efficacy as follows: (5‐fluorouracil = imiquimod = carbon dioxide laser resurfacing = Er:YAG laser resurfacing = ALA‐PDT = MAL‐PDT = trichloroacetic acid peel = diclofenac ) > masoprocol (cryotherapy = betulin‐based oleogel). The relative efficacy between masoprocol and cryotherapy was not investigated in any of the studies included. In summary, the comparisons of different interventions showed that these interventions were generally comparable.
In our review, carbon dioxide laser resurfacing has been shown to have a similar efficacy to 5‐fluorouracil and trichloroacetic acid peel to treat actinic keratosis. However, the efficiency of carbon dioxide laser resurfacing to prevent short‐term (within 12 months) recurrence of actinic keratoses has been questioned (Fulton 1999). Because recurrence, prophylaxis of actinic keratoses, or both, were not in the prespecified outcomes of our review, we will not further discuss this matter, but there might be a need for a future review on the subject.
The relative efficacy of the interventions on various anatomical locations was poorly reported. The majority of studies that investigated different regions of the skin grouped the locations together for each outcome. The only significant difference was reported between lesions on the face and upper extremities during isotretinoin treatment. There was also a decreased tendency to favour imiquimod for the lesions on the face. In summary, there was insufficient data to determine the difference in the lesions' location in this meta‐analysis.
For three interventions, the efficacy relative to vehicle/placebo was investigated in immunosuppressed participants. Data from only one study with a small sample was usually included for immunosuppressed participants in the analyses, whereas data from several studies was generally pooled for immunocompetent participants. Thus, it is difficult to compare directly the calculated risk ratios and their 95% CI between studies including immunocompetent versus immunosuppressed participants. A comparison of the unweighted 'participant complete clearance' rates suggests that a similar efficacy is achieved for the two populations. In immunocompetent participants, diclofenac resulted in a 32% (67/208) complete clearance, whereas vehicle had a 13% (27/212) clearance. In immunosuppressed participants the same rates were 41% (9/66) for diclofenac and 0% (0/6) for vehicle. Imiquimod (5%) resulted in 42% (694/1649) vs 62% (18/29) complete clearance, whereas vehicle resulted in 5% (62/1231) and 0% (0/14) for the immunocompetent and immunosuppressed groups, respectively. In PDT, 76% (13/17) of immunosuppressed participants and 74% (204/278) of immunocompetent participants were completely cleared with MAL‐PDT compared to 14% (30/204) and 0% (0/17) for placebo‐PDT. In summary, the treatments were equally efficacious in immunosuppressed and immunocompetent participants. One ongoing study (NCT01525329) is comparing treatment with MAL‐PDT alone and in combination with 5% 5‐fluorouracil in both immunocompetent and immunosuppressed participants.
Secondary outcomes
In general, the number of participants withdrawn because of adverse events was not significantly different between interventions. The only exceptions were the following:
-
3% diclofenac in 2.5% hyaluronic acid compared to 2.5% hyaluronic acid (see overview for diclofenac in Table 1),
-
5% imiquimod compared to placebo (see overview for imiquimod Table 5), and
-
0.06% to 0.1% resiquimod compared to 0.01% to 0.03% resiquimod.
The studies reporting skin irritation indicate that diclofenac (see overview for diclofenac in Table 1), 5‐fluorouracil (see overview for 5‐fluorouracil in Table 2), tretinoin, isotretinoin, and ALA (see overview for photodynamic therapy in Table 3) treatments are associated with significant skin irritation. Topical treatments were associated with different adverse effects than photodynamic therapy and cryotherapy. Topical treatments were associated with "flu" or "cold" symptoms, headache, and conjunctivitis or eye irritation. Photodynamic therapy and cryotherapy were associated with photosensitivity reaction and cold exposure injury, respectively. Most of the minor adverse events that were quantitatively reported were not significantly different between the two interventions that were compared. The only exceptions were the dermatitis associated with adapalene, the metabolic and nutritional disorder and dry skin associated with diclofenac, the "flu" or "cold" symptoms and headache with daily application of imiquimod, and the headache associated with concentrations of resiquimod superior to 0.01%.
Finally, the included studies reported varied cosmetic outcomes. In general, it could be concluded that imiquimod treatment and photodynamic therapy resulted in better cosmetic outcomes than cryotherapy and 5‐fluorouracil.
Overall completeness and applicability of evidence
The physician's decision about which treatment to prescribe will depend on each patient's case and their treatment aims. Different interventions might be more effective for cosmetic outcomes, symptom relief, or prevention of squamous cell carcinoma. In addition, the efficacy, cost, adverse events, length of treatment, ease of treatment, personal preference of the participant, participant compliance, severity of actinic damage, past treatment experiences, and other factors must all be taken into consideration, and the most appropriate treatment will vary from person to person. The completeness of this review will be discussed based on these factors influencing the choice of an intervention for treating actinic keratoses.
Several of these factors (cost, ease of treatment, participant preference, participant compliance, past treatment experiences) were not included in this review. Some of these factors were presented as outcomes in a few studies, and these are summarised in a table in the Included studies section under 'other outcomes'.
This review included several efficacy outcomes. However, the exclusion of an important efficacy outcome, such as 'lesion complete response', limited the evaluation of the relative efficacy of several interventions because some studies only reported this efficacy outcome (see Effects of interventions).
Adverse event reporting was complicated by the use of the generic "skin irritation" outcome. Many studies chose to use categories such as "application site reactions" and "local skin/adverse reactions" instead of "skin irritation".
The interventions could also be compared based on their length of treatment. A wide variety of treatment options are available for actinic keratosis. Treatments such as cryotherapy or photodynamic therapy are performed once or twice by clinical staff, whereas the duration of topical treatments administered by patients varies from two applications within a few days for ingenol mebutate to daily application for seven months with sunscreen. A decision based on patient compliance and preference could easily be made. The effect of changing the length of a specific treatment was reported in this review where the information was available, but we did not compare different interventions based on their length of treatment. We did not compare continuous therapy with interval/pulse/cycle therapy. The readers are referred to a recent review (Martin 2011), which discusses the efficacy of short‐course and interval/pulse/cycle therapies for 5‐fluorouracil, imiquimod, and ALA/MAL‐PDT. Outcomes reported over time showed differences between the assessments, but variations in the time of the assessment (follow‐up period) were generally not taken into consideration in our evaluation of the relative efficacy between interventions. Long‐term (> one year) outcomes were not included in our meta‐analysis, but references to these studies were included in the 'Characteristics of included studies' tables.
The severity of the lesions at baseline was not accounted for in our analysis. The studies reported the severity of lesions in different terms; some used the lesion grade, whereas others reported the number of lesions. In some studies, the number of lesions was a criterion for inclusion or exclusion of participants. This information can be found for the individual studies in the 'Characteristics of included studies' tables in the 'participants' sections.
Many patients wish to have their actinic keratoses treated in order to prevent their development into squamous cell carcinoma. The detection of squamous cell carcinoma, basal cell carcinoma, or Bowen's disease was not included in our outcomes, and little is known about their prevention by treating actinic keratoses. This outcome should be addressed in the future. One ongoing study (NCT01453179) will evaluate this issue for 5% imiquimod and 3% diclofenac in hyaluronic acid. However, it is worth noting that the studies included in our analysis did not specify if cancerous lesions were present in the treatment area. This makes the interpretation of this data difficult.
Quality of the evidence
The quality of the evidence presented in this review was evaluated in the 'Risk of bias' graph (Figure 2) and the 'Risk of bias' tables associated with each included study. The major factors decreasing the quality of evidence from the studies on interventions for actinic keratoses are as follows:
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lack of reporting the methods used for allocation sequence generation and allocation concealment;
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blinding of studies comparing physically‐distinct interventions;
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the use of per‐protocol (PP) analysis instead of intention‐to‐treat (ITT) analysis (but PP data were converted as much as possible to ITT for meta‐analyses); and
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incomplete reporting of an outcome.
We also noticed another issue with reporting the diagnosis criteria for inclusion of the participants (see 'Characteristics of included studies' tables). Many studies did not specify whether a clinical or histological diagnosis was used to include the participants in the clinical trials.
There were two major limitations in our assessment of the effects of interventions for actinic keratoses. The first was that data from numerous intraindividual studies could not be included in the meta‐analyses. The second was the frequent omission of standard deviations in the reporting of the outcome "mean reduction in lesion counts" for both absolute values and percentages, which prevented the statistical analysis of the data. Without the standard deviations, it is difficult to determine if there is a difference between the intervention and the control intervention.
The studies included in the different meta‐analyses were generally very consistent, and only a few examples of high heterogeneity were observed. Many of the analyses only included data from an individual study; this included 76% of the efficacy outcomes, 91% of the safety outcomes, and 87% of the cosmetic outcomes.
The frequency of high‐quality studies varied based on treatment. Our inclusion criteria fit more studies on imiquimod than 5‐fluorouracil or cryotherapy. In contrast, 5‐fluorouracil and cryotherapy have been compared to more interventions than imiquimod. The nature of cryotherapy does not allow for double‐blinded prospective trials, with the exception of studies investigating the combined therapy with a topical treatment, which resulted in lower quality evidence (see overview for cryotherapy in Table 4).
There were several biases that affected the quality of the evidence. Certain treatments incurred adverse skin reactions (e.g. imiquimod, 5‐fluorouracil, ALA, etc) that may indirectly introduce bias into the clinical assessment. Moreover, when comparing self‐administered and clinically‐administered interventions, such as 5‐fluorouracil and photodynamic therapy, the compliance of the participants could have an influence on the outcomes and could introduce selection bias if participants were included or excluded based on their compliance. Reporting bias could also result from the method used to assess efficacy outcomes. Several studies reported the observation of new actinic keratoses during the clinical trial, and most of the studies did not specify whether they were studying all lesions or a specific subpopulation of clinical, subclinical, or new lesions.
Potential biases in the review process
This review included a broad variety of interventions for actinic keratoses and a large number of outcomes. The search for corresponding studies resulted in a large number of studies, which produced a considerable amount of information. Data extraction sheets were really useful tools for the organisation of this information. However, important details for comparison between studies could have been missed or overlooked in this process. The amount of information presented meant that we were unable to evaluate all of the factors influencing the outcomes, including the methods used for assessment. We searched multiple databases as well as websites and grey literature for randomised clinical trials on all interventions (not prophylaxis) for actinic keratoses in any language. We also contacted pharmaceutical companies to request additional information, but this correspondence was not always successful. There is a possibility that studies may be missing. For example, a study on comparison between 5% 5‐fluorouracil and placebo for solar keratoses was registered in the metaRegister of Controlled Trials (mRCT) in 2001 to 2002, but no publication of this study was found.
Our analysis only included randomised controlled trials due to the large scope of this review; all other trial designs were excluded. The randomised clinical trials were only included if all the interventions were covered by this review and if they reported numerical results for at least one of the review outcomes. This criterion excluded the outcome 'Withdrawal due to adverse events', which is generally reported in all the studies. Because the terminology used for the different outcomes was not always consistent in the studies (see the Included studies section under 'Outcomes'), the interpretation of the outcomes' definitions could have introduced some bias in the review process.
Inconsistency in terminology could also have led to misinterpretation during the data extraction process. Some of the review outcomes have been redefined to try to avoid this problem. However, a more precise definition of some outcomes was not always possible. There does not seem to be a common definition of "skin irritation", and many studies included adverse event outcomes that included irritation, symptoms of irritation, or both. The lack of consensus on which symptoms constitute "skin irritation" and the potential for different interpretations by the authors of the studies has resulted in our decision to only include outcomes with the word "irritation" in the label. This adverse event category may also include a pooling of different outcomes, as the skin irritation was not identified by the site (application site vs local irritation).
We separated the studies into two populations of participants: immunocompetent and immunosuppressed. We considered participants to be immunocompetent by default if the studies did not specifically include immunosuppressed participants. However, in 40% of these studies, immunosuppressed participants could have been enrolled based on the inclusion and exclusion criteria reported. It is possible that the immunocompetent population included few immunosuppressed participants.
Data from intention‐to‐treat analysis was used in the analysis for the review whenever possible to reduce the attrition bias and increase consistency between studies included in the same meta‐analysis. The information provided in the studies did not always allow for the conversion of data from per‐protocol analysis to intention‐to‐treat analysis. In some studies, the authors did not observe a significant difference in the outcomes when analysis was conducted with per‐protocol analysis, as opposed to intention‐to‐treat analysis. Thus, the estimated effect size calculated in the meta‐analyses should not be affected and our conclusions should remain unchanged. Several studies presented data in a graphical format that was not included in our analysis, either because of unsuccessful correspondence with the authors, time limitations, or both. Statistical limitations due to outcome without event, such as exclusion from meta‐analysis or calculation for number needed to treat (NNT) based on assumed control risk (ACR), also restricted our analyses and conclusions.
Agreements and disagreements with other studies or reviews
In a systematic review of randomised controlled trials using 0.5% and 5% 5‐fluorouracil for treatment of actinic keratoses, 9 studies were identified (Kaur 2010). We included seven of these studies in our review and excluded two because there was no clear mention of randomisation of the treatments in the published reports. Despite this difference, the authors arrived at a similar conclusion to our review about the participant complete clearance of the 2 concentrations of 5‐fluorouracil. In another systematic review (Askew 2009), the authors estimated that about 500 of 1000 of participants receiving 5‐fluorouracil for treatment of actinic keratoses could expect complete clearance. An average of our illustrative comparative risks based on study population for 0.5% and 5% 5‐fluorouracil treatments (see overview for 5‐fluorouracil in Table 2) resulted in 577 of 1000 participants with complete clearance. A similar conclusion was reached by using different methodologies.
A meta‐analysis of 5 full journal publications of randomised double‐blind clinical trials comparing 5% imiquimod to vehicle concluded that about 50% of participants (500 of 1000) treated with 5% imiquimod achieved complete clearance (Hadley 2006). In this review, the method used to pool data was not specified (but the numbers given suggested that the numbers were added together without any weighting) and a fixed‐effect model was used to calculate the relative risk. Our review calculated a lower percentage of 25% to 38% (253 to 382 of 1000; see overview for imiquimod in Table 5) based on 9 studies using a random‐effects model to calculate the pooled risk ratio (RR). In contrast to our review, Hadley 2006 did not find any difference in the number of withdrawals due to adverse events between 5% imiquimod and vehicle, but a difference was detected for withdrawal in general, with significantly more in the imiquimod group. Hadley et al detected a greater proportion of local, treatment‐related, and overall adverse effects in the 5% imiquimod group, but did not observe any differences in serious adverse events. Thus, 5% imiquimod treatment is generally associated with more adverse events than vehicle.
In a systematic review on photodynamic therapy in the treatment of pre‐cancerous skin conditions and cancers (Fayter 2010), the authors reached the following conclusions for the treatment of actinic keratosis: 1) "The only clear evidence of effectiveness" came from the comparison of ALA/MAL‐PDT and placebo‐PDT, and 2) "Uncertainties still exist around PDT’s effectiveness compared with other topical treatments." Our analyses led to similar conclusions (see the overview for photodynamic therapy in Table 3).
In our review, the efficacy of ALA‐PDT was superior to cryotherapy based on 'participant complete clearance', but the efficacy of MAL‐PDT compared to cryotherapy could not be assessed. A meta‐analysis of 'lesion complete response' was performed in the Fayter 2010 review to compare MAL‐PDT to cryotherapy. Unfortunately, this analysis included 4 studies with high heterogeneity (I² statistic = 88%), and no definitive conclusion could be made on their relative efficacy. The authors of this review also concluded that the improved cosmetic outcomes obtained for PDT compared to cryotherapy might be due to bias, because in most of the studies the assessors were not blinded.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Funnel plot of comparison: 15 Imiquimod versus placebo: different concentrations, outcome: 15.1 Participant complete clearance.
Funnel plot of comparison: 50 MAL‐PDT (red light) versus placebo‐PDT (red light), outcome: 50.1 Participant complete clearance.
Comparison 1 Adapalene gel versus placebo, Outcome 1 Global Improvement Indices (investigator)‐cleared.
Comparison 1 Adapalene gel versus placebo, Outcome 2 Mean changes in lesion counts.
Comparison 1 Adapalene gel versus placebo, Outcome 3 Withdrawal due to adverse events.
Comparison 1 Adapalene gel versus placebo, Outcome 4 Minor adverse events excluding skin irritation: dermatitis.
Comparison 2 0.1% adapalene vs 0.3% adapalene, Outcome 1 Global Improvement Indices (investigator)‐cleared.
Comparison 2 0.1% adapalene vs 0.3% adapalene, Outcome 2 Mean changes in lesion counts.
Comparison 2 0.1% adapalene vs 0.3% adapalene, Outcome 3 Withdrawal due to adverse events.
Comparison 2 0.1% adapalene vs 0.3% adapalene, Outcome 4 Minor adverse events excluding skin irritation: dermatitis.
Comparison 3 Arotinoid Methyl Sulfone (Ro 14‐9706) versus Tretinoin, Outcome 1 Mean percentage of reduction in lesion counts.
Comparison 4 Calcipotriol (vitamin D) versus placebo, Outcome 1 Mean changes in lesion counts.
Comparison 4 Calcipotriol (vitamin D) versus placebo, Outcome 2 Cosmetic outcomes: Reduction in total cosmetic appearance score.
Comparison 5 1% colchicine cream versus 0.5% colchicine cream, Outcome 1 Participant complete clearance.
Comparison 5 1% colchicine cream versus 0.5% colchicine cream, Outcome 2 Mean reduction in lesion counts‐total.
Comparison 5 1% colchicine cream versus 0.5% colchicine cream, Outcome 3 Mean reduction in lesion counts‐per anatomical locations.
Comparison 5 1% colchicine cream versus 0.5% colchicine cream, Outcome 4 Cosmetic outcomes: Number of participants with decreased infiltration and disappearance of crust.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 1 Investigator Global Improvement Indices‐completely improved.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 2 Participant Global Improvement Indices‐completely improved.
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).
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 4 Participant complete clearance (target lesions).
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 5 Participant complete clearance (all lesions).
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.
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.
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.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 9 Participant complete clearance in immunosuppressed participants.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 10 Participant partial (>75%) clearance in immunosuppressed participants.
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.
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.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 13 Withdrawal due to adverse events.
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.
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".
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.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 17 Minor adverse event: cardiovascular: in general.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 18 Minor adverse event: cardiovascular: sinus bradycardia.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 19 Minor adverse event: dermatological: bursitis.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 20 Minor adverse event: dermatological: dry skin.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 21 Minor adverse event: dermatological: herpes zoster.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 22 Minor adverse event: dermatological: rash vesiculobullous.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 23 Minor adverse event::dermatological: seborrhoea.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 24 Minor adverse event: dermatological: skin exfoliation.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 25 Minor adverse event: dermatological: ulcerated skin.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 26 Minor adverse event: digestive : in general.
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.
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.
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.
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.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 31 Minor adverse event: nervous system: in general.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 32 Minor adverse event: nervous system: headache.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 33 Minor adverse event: nervous system: hyperaesthesia.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 34 Minor adverse event: nervous system: paraesthesia.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 35 Minor adverse event: respiratory: in general.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 36 Minor adverse event: respiratory: bronchitis.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 37 Minor adverse event: respiratory: pharyngitis.
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.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 39 Minor adverse event: special senses: in general.
Comparison 6 3% diclofenac in 2.5% hyaluronic acid versus 2.5% hyaluronic acid (vehicle), Outcome 40 Minor adverse event: urogenital: in general.
Comparison 7 3% diclofenac in 2.5% hyaluronic acid versus 5% imiquimod, Outcome 1 Investigator Global Improvement Indices‐Complete improvement.
Comparison 7 3% diclofenac in 2.5% hyaluronic acid versus 5% imiquimod, Outcome 2 Participant Global Improvement Indices‐Complete improvement.
Comparison 8 2‐(Difluoromethyl)‐dl‐ornithine (DFMO) versus placebo, Outcome 1 Mean reduction in lesions counts.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 1 Participant complete clearance.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 2 Mean reduction in lesion counts.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 3 Mean percentage of reduction in lesion counts.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 4 Withdrawal due to adverse events.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 5 Skin irritation.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 6 Minor adverse event excluding skin irritation: body as a whole : in general.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 7 Minor adverse event excluding skin irritation: body as a whole : allergy.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 8 Minor adverse event excluding skin irritation: body as a whole : "flu" or common cold.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 9 Minor adverse event excluding skin irritation: musculoskeletal and connective tissue: in general.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 10 Minor adverse event excluding skin irritation: musculoskeletal and connective tissue: soreness.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 11 Minor adverse event excluding skin irritation:nervous system: headache.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 12 Minor adverse event excluding skin irritation: respiratory: in general.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 13 Minor adverse event excluding skin irritation: respiratory: sinusitis.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 14 Minor adverse event excluding skin irritation: respiratory: upper respiratory tract infection.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 15 Minor adverse event excluding skin irritation: special senses: in general.
Comparison 9 0.5% 5‐FU versus vehicle, Outcome 16 Minor adverse event excluding skin irritation:special senses: eye irritation.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 1 Participant complete clearance.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 2 Withdrawal due to adverse events.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 3 Skin irritation.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 4 Minor adverse events excluding skin irritation: body as a whole : in general.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 5 Minor adverse events excluding skin irritation: body as a whole : allergy.
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.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 7 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 8 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 9 Minor adverse events excluding skin irritation: respiratory: in general.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 10 Minor adverse events excluding skin irritation: respiratory: sinusitis.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 11 Minor adverse events excluding skin irritation: special senses: in general.
Comparison 10 0.5% 5‐FU at varying application durations, Outcome 12 Minor adverse events excluding skin irritation: special senses: eye irritation.
Comparison 11 0.5% 5‐FU versus ALA‐PDT, Outcome 1 Participant complete clearance.
Comparison 11 0.5% 5‐FU versus ALA‐PDT, Outcome 2 Withdrawal due to adverse events.
Comparison 12 5% 5‐FU with 0.05% tretinoin versus 5% 5‐FU with placebo, Outcome 1 Mean reduction in lesion counts.
Comparison 13 5% 5‐FU versus 5% imiquimod, Outcome 1 Participant complete clearance.
Comparison 14 5% 5‐FU versus cryotherapy, Outcome 1 Participant complete clearance.
Comparison 15 5% 5‐FU versus 10% masoprocol, Outcome 1 Investigator Global Improvement Indices ‐cleared.
Comparison 15 5% 5‐FU versus 10% masoprocol, Outcome 2 Mean reduction of lesion counts.
Comparison 15 5% 5‐FU versus 10% masoprocol, Outcome 3 Mean percentage of reduction of lesion counts.
Comparison 15 5% 5‐FU versus 10% masoprocol, Outcome 4 Withdrawal due to adverse events.
Comparison 16 5% 5‐FU versus carbon dioxide laser resurfacing, Outcome 1 Mean percentage of reduction of lesion counts.
Comparison 16 5% 5‐FU versus carbon dioxide laser resurfacing, Outcome 2 Withdrawal due to adverse events.
Comparison 17 5% 5‐FU versus Er:YAG laser resurfacing, Outcome 1 Withdrawal due to adverse events.
Comparison 17 5% 5‐FU versus Er:YAG laser resurfacing, Outcome 2 Skin irritation.
Comparison 18 5% 5‐FU versus Trichloroacetic acid peel, Outcome 1 Mean percentage of reduction in lesions.
Comparison 19 5% Imiquimod versus placebo, Outcome 1 Participant complete clearance‐number of doses.
Comparison 19 5% Imiquimod versus placebo, Outcome 2 Participant complete clearance in immunosuppressed participants.
Comparison 19 5% Imiquimod versus placebo, Outcome 3 Participant partial (>75%) clearance.
Comparison 19 5% Imiquimod versus placebo, Outcome 4 Participant partial (>75%) clearance in immunosuppressed participants.
Comparison 19 5% Imiquimod versus placebo, Outcome 5 Mean reduction in lesion counts.
Comparison 19 5% Imiquimod versus placebo, Outcome 6 Withdrawal due to adverse events.
Comparison 19 5% Imiquimod versus placebo, Outcome 7 Withdrawal due to adverse events in immunosuppressed participants.
Comparison 19 5% Imiquimod versus placebo, Outcome 8 Minor adverse events excluding skin irritation: body as a whole: in general.
Comparison 19 5% Imiquimod versus placebo, Outcome 9 Minor adverse events excluding skin irritation: body as a whole: "flu" or "cold".
Comparison 19 5% Imiquimod versus placebo, Outcome 10 Minor adverse events excluding skin irritation: digestive: in general.
Comparison 19 5% Imiquimod versus placebo, Outcome 11 Minor adverse events excluding skin irritation: digestive: nausea.
Comparison 19 5% Imiquimod versus placebo, Outcome 12 Minor adverse events excluding skin irritation: nervous system: in general.
Comparison 19 5% Imiquimod versus placebo, Outcome 13 Cosmetic outcome: decrease in roughness/dryness/scaliness of the skin.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 1 Participant complete clearance.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 2 Participant partial (>75%) clearance.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 3 Mean percentage of reduction in lesion counts.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: 'flu" or "cold".
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 5 Withdrawal due to adverse events.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 6 Skin irritation.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 7 Minor adverse events excluding skin irritation: body as a whole: pyrexia.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 8 Minor adverse events excluding skin irritation: hemic and lymphatic: lymphadenopathy.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 9 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 10 Minor adverse events excluding skin irritation: nervous system: fatigue.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 11 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 12 Minor adverse events excluding skin irritation: respiratory: cough.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 13 Minor adverse events excluding skin irritation: respiratory: sinusitis.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 14 Minor adverse events excluding skin irritation: respiratory: upper respiratory tract infection.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 15 Minor adverse events excluding skin irritation: urogenital: urinary tract infection.
Comparison 20 Imiquimod versus placebo: different concentrations, Outcome 16 Cosmetic outcome: Participant's significantly or much improved cosmetic outcome assessed by investigator.
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 1 Participant complete clearance.
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 2 Participant partial (>75%) clearance.
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 3 Withdrawal due to adverse events.
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 4 Minor adverse events excluding skin irritation:body as a whole: in general.
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 5 Minor adverse events excluding skin irritation: body as a whole:"flu" or "cold".
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 6 Minor adverse events excluding skin irritation: digestive: in general.
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 7 Minor adverse events excluding skin irritation: digestive: nausea.
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 8 Minor adverse events excluding skin irritation: nervous system: in general.
Comparison 21 Imiquimod versus placebo: frequency of application, Outcome 9 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 22 5% imiquimod versus 5% 5‐FU, Outcome 1 Participant complete clearance.
Comparison 22 5% imiquimod versus 5% 5‐FU, Outcome 2 Cosmetic outcome: Investigator cosmetic outcome "excellent".
Comparison 22 5% imiquimod versus 5% 5‐FU, Outcome 3 Cosmetic outcome: normal skin surface.
Comparison 23 5% imiquimod versus cryotherapy, Outcome 1 Participant complete clearance.
Comparison 24 Ingenol mebutate (PEP005) versus placebo, Outcome 1 Participant complete clearance of target lesions.
Comparison 24 Ingenol mebutate (PEP005) versus placebo, Outcome 2 Participant complete clearance of all lesions.
Comparison 24 Ingenol mebutate (PEP005) versus placebo, Outcome 3 Participant partial (>75%) clearance of target lesions.
Comparison 24 Ingenol mebutate (PEP005) versus placebo, Outcome 4 Cosmetic outcomes: changes in pigmentation.
Comparison 25 Ingenol mebutate (PEP005) versus placebo: different concentrations, Outcome 1 Participant complete clearance of target lesions.
Comparison 25 Ingenol mebutate (PEP005) versus placebo: different concentrations, Outcome 2 Participant complete clearance of all lesions.
Comparison 25 Ingenol mebutate (PEP005) versus placebo: different concentrations, Outcome 3 Participant partial (>75%) clearance of target lesions.
Comparison 25 Ingenol mebutate (PEP005) versus placebo: different concentrations, Outcome 4 Cosmetic outcomes: changes in pigmentation.
Comparison 26 0.05% Ingenol mebutate (PEP005) versus placebo: number of doses, Outcome 1 Participant complete clearance of target lesions.
Comparison 26 0.05% Ingenol mebutate (PEP005) versus placebo: number of doses, Outcome 2 Participant complete clearance of all lesions.
Comparison 26 0.05% Ingenol mebutate (PEP005) versus placebo: number of doses, Outcome 3 Participant partial (>75%) clearance of target lesions.
Comparison 27 Isotretinoin versus vehicle, Outcome 1 Investigator global improvement indices‐completely cleared.
Comparison 27 Isotretinoin versus vehicle, Outcome 2 Mean reduction of lesion counts.
Comparison 27 Isotretinoin versus vehicle, Outcome 3 Withdrawal due to adverse events.
Comparison 27 Isotretinoin versus vehicle, Outcome 4 Skin irritation.
Comparison 27 Isotretinoin versus vehicle, Outcome 5 Severe‐Skin irritation.
Comparison 28 Masoprocol versus placebo, Outcome 1 Global improvement indices‐cured.
Comparison 28 Masoprocol versus placebo, Outcome 2 Mean reduction in lesion counts.
Comparison 28 Masoprocol versus placebo, Outcome 3 Withdrawal due to adverse events.
Comparison 29 1% nicotinamide versus placebo, Outcome 1 Mean percentage of reduction in lesion counts.
Comparison 29 1% nicotinamide versus placebo, Outcome 2 Withdrawal due to adverse events.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 1 Participant complete clearance.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 2 Participant partial (>75%) clearance.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 3 Withdrawal due to adverse events.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
Comparison 30 0.1% resiquimod versus 0.01% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 1 Participant complete clearance.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 2 Participant partial (>75%) clearance.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 3 Withdrawal due to adverse events.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
Comparison 31 0.1% resiquimod versus 0.03% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 1 Participant complete clearance.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 2 Participant partial (>75%) clearance.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 3 Withdrawal due to adverse events.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
Comparison 32 0.1% resiquimod versus 0.06% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 1 Participant complete clearance.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 2 Participant partial (>75%) clearance.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 3 Withdrawal due to adverse events.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
Comparison 33 0.06% resiquimod versus 0.01% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 1 Participant complete clearance.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 2 Participant partial (>75%) clearance.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 3 Withdrawal due to adverse events.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
Comparison 34 0.06% resiquimod versus 0.03% resiquimod, Outcome 13 Minor adverse events excluding skin irritation:skin and subcutaneous disorders: in general.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 1 Participant complete clearance.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 2 Participant partial (>75%) clearance.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 3 Withdrawal due to adverse events.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 4 Minor adverse events excluding skin irritation: body as a whole: fatigue.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 5 Minor adverse events excluding skin irritation: body as a whole: rigors.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 9 Minor adverse events excluding skin irritation: nervous system: in general.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 10 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 11 Minor adverse events excluding skin irritation: nervous system: lethargy.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders.
Comparison 35 0.03% resiquimod versus 0.01% resiquimod, Outcome 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general.
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.
Comparison 37 12.5% DL‐α‐tocopherol (vitamin E) versus placebo, Outcome 1 Mean reduction of lesion counts.
Comparison 38 Etretinate versus placebo, Outcome 1 Participant complete clearance.
Comparison 39 Carbon dioxide laser resurfacing versus 5% 5‐FU, Outcome 1 Mean percentage of reduction of lesion counts.
Comparison 39 Carbon dioxide laser resurfacing versus 5% 5‐FU, Outcome 2 Withdrawal due to adverse events.
Comparison 40 Carbon dioxide laser resurfacing versus Trichloroacetic acid peel, Outcome 1 Mean percentage of reduction of lesion counts.
Comparison 40 Carbon dioxide laser resurfacing versus Trichloroacetic acid peel, Outcome 2 Withdrawal due to adverse events.
| Study | Intervention | At 3 months | At 6 months | At 12 months |
| Ostertag 2006 | 5‐fluorouracil | 13.2 | 12.5 | 12.4 |
| Ostertag 2006 | Er:YAG laser resurfacing | 13.8 | 13.9 | 14.2 |
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 1 Mean reduction in lesion counts.
| Study | Assessment | Resurfacing | 5‐FU |
| Ostertag 2006 | At 6 months | 94.4% | 79.2% |
| Ostertag 2006 | At 12 months | 91.1% | 76.6% |
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 2 Mean percentage of reduction in lesion counts.
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 3 Withdrawal due to adverse events.
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 4 Skin irritation.
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 5 Minor adverse events excluding skin irritation: dermatology: acne.
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 6 Minor adverse events excluding skin irritation: dermatology:crustea.
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 7 Minor adverse events excluding skin irritation: dermatology: infection.
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 8 Minor adverse events excluding skin irritation: dermatology: milia.
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 9 Minor adverse events excluding skin irritation: dermatology:pain.
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 10 Cosmetic outcomes: changes in pigmentation (hypo).
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 11 Cosmetic outcomes: scarring.
Comparison 41 Er:YAG laser resurfacing versus 5% 5‐FU, Outcome 12 Cosmetic outcomes: improvement in photoageing score.
Comparison 42 Cryotherapy versus betulin‐based oleogel, Outcome 1 Participant complete clearance.
Comparison 42 Cryotherapy versus betulin‐based oleogel, Outcome 2 Participant partial (>75%) clearance.
Comparison 43 Cryotherapy versus 5% 5‐FU, Outcome 1 Participant complete clearance.
Comparison 43 Cryotherapy versus 5% 5‐FU, Outcome 2 Cosmetic outcomes: excellent global cosmetic outcome.
Comparison 43 Cryotherapy versus 5% 5‐FU, Outcome 3 Cosmetic outcomes: better skin appearance.
Comparison 44 Cryotherapy versus imiquimod, Outcome 1 Participant complete clearance.
Comparison 44 Cryotherapy versus imiquimod, Outcome 2 Cosmetic outcomes: excellent global cosmetic outcome.
Comparison 44 Cryotherapy versus imiquimod, Outcome 3 Cosmetic outcomes: better skin appearance.
| Study | Assessment at | Cryotherapy | MAL‐PDT |
| Kaufmann 2008 | 12 weeks | N/A | N/A |
| Kaufmann 2008 | 24 weeks | 87% | 75% |
| Morton 2006 | 12 weeks | 74.5% | 84.4% |
| Morton 2006 | 24 weeks | 83.9% | 86.7% |
Comparison 45 Cryotherapy versus MAL‐red light PDT, Outcome 1 Mean percentage of reduction in lesion counts.
Comparison 45 Cryotherapy versus MAL‐red light PDT, Outcome 2 Withdrawal due to adverse events.
Comparison 45 Cryotherapy versus MAL‐red light PDT, Outcome 3 Cosmetic outcomes: excellent or good cosmetic outcomes by investigator.
Comparison 45 Cryotherapy versus MAL‐red light PDT, Outcome 4 Cosmetic outcomes: excellent or good cosmetic outcomes by participant.
Comparison 46 Cryotherapy versus ALA‐red light PDT, Outcome 1 Participant complete clearance.
Comparison 46 Cryotherapy versus ALA‐red light PDT, Outcome 2 Skin irritation.
![Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 1 Participant complete clearance [1 treatment].](/cdsr/doi/10.1002/14651858.CD004415.pub2/media/CDSR/CD004415/image_n/nCD004415-CMP-047-01.png)
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 1 Participant complete clearance [1 treatment].
![Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 2 Participant complete clearance [1 or 2 treatments].](/cdsr/doi/10.1002/14651858.CD004415.pub2/media/CDSR/CD004415/image_n/nCD004415-CMP-047-02.png)
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 2 Participant complete clearance [1 or 2 treatments].
![Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 3 Participant complete clearance [1 or 2 treatments] by anatomical location.](/cdsr/doi/10.1002/14651858.CD004415.pub2/media/CDSR/CD004415/image_n/nCD004415-CMP-047-03.png)
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 3 Participant complete clearance [1 or 2 treatments] by anatomical location.
![Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 4 Participant partial (> 75%) clearance [1 treatment].](/cdsr/doi/10.1002/14651858.CD004415.pub2/media/CDSR/CD004415/image_n/nCD004415-CMP-047-04.png)
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 4 Participant partial (> 75%) clearance [1 treatment].
![Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 5 Participant partial (>75%) clearance[1 or 2 treatments].](/cdsr/doi/10.1002/14651858.CD004415.pub2/media/CDSR/CD004415/image_n/nCD004415-CMP-047-05.png)
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 5 Participant partial (>75%) clearance[1 or 2 treatments].
![Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 6 Participant partial (>75%) clearance [1 or 2 treatment] by anatomical location.](/cdsr/doi/10.1002/14651858.CD004415.pub2/media/CDSR/CD004415/image_n/nCD004415-CMP-047-06.png)
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 6 Participant partial (>75%) clearance [1 or 2 treatment] by anatomical location.
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 7 Skin irritation.
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 8 Minor adverse events excluding skin irritation: body as a whole: injury.
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 9 Minor adverse events excluding skin irritation: cardiovascular: hypertension.
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 10 Minor adverse events excluding skin irritation: dermatology: skin discolouration.
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 11 Minor adverse events excluding skin irritation: dermatology: skin hypertrophy.
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 12 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 47 ALA‐PDT versus placebo‐PDT, Outcome 13 Cosmetic outcome: very good or good general cosmetic outcome.
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 1 Participant complete clearance.
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 2 Participant partial (>75%) clearance.
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 3 Cosmetic outcome: improvement in global response.
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 4 Cosmetic outcome: improvement in tactile roughness.
Comparison 48 ALA‐ blue light PDT versus ALA‐pulsed laser PDT, Outcome 5 Cosmetic outcome: improvement in mottled hyperpigmentation.
Comparison 49 ALA‐red light PDT at different application times, Outcome 1 Participant complete clearance at 4 weeks.
Comparison 49 ALA‐red light PDT at different application times, Outcome 2 Participant complete clearance at 8 weeks.
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).
Comparison 49 ALA‐red light PDT at different application times, Outcome 4 Minor adverse events excluding skin irritation: nervous system: headache.
Comparison 49 ALA‐red light PDT at different application times, Outcome 5 Minor adverse events excluding skin irritation: other: epistaxis (nose bleeding).
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 1 Participant complete clearance.
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 2 Participant partial (>75%) clearance.
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 3 Withdrawal due to adverse events.
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 4 Cosmetic outcome: improvement in global response.
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 5 Cosmetic outcome: improvement in tactile roughness.
Comparison 50 ALA‐PDT versus 0.5% 5‐FU, Outcome 6 Cosmetic outcome: improvement in mottled hyperpigmentation.
Comparison 51 ALA‐red light PDT vs cryotherapy, Outcome 1 Participant complete clearance.
Comparison 51 ALA‐red light PDT vs cryotherapy, Outcome 2 Skin irritation.
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 1 Participant complete clearance.
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 2 Participant partial (>75%) clearance.
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 3 Withdrawal due to adverse events.
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 4 Minor adverse event: nervous system: headache.
Comparison 52 MAL‐red light PDT versus placebo‐red light PDT, Outcome 5 Cosmetic outcome: hyperpigmentation.
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.
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.
Comparison 54 MAL‐red light LED PDT versus MAL‐daylight PDT, Outcome 1 Mean reduction in lesion counts.
Comparison 55 2h MAL‐day light PDT versus 3h MAL‐daylight PDT, Outcome 1 Mean reduction in lesion counts.
Comparison 55 2h MAL‐day light PDT versus 3h MAL‐daylight PDT, Outcome 2 Mean percentage of reduction in lesion counts.
Comparison 56 16% MAL‐daylight PDT versus 8% MAL‐daylight PDT, Outcome 1 Mean reduction in lesion counts.
Comparison 57 Single MAL‐red light PDT versus multiple MAL‐red light PDT (2 treatments 1 week apart), Outcome 1 Participant complete clearance.
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.
Comparison 58 MAL‐ red light PDT vs cryotherapy, Outcome 1 Withdrawal due to adverse events.
Comparison 59 ALA‐red light PDT versus MAL‐red light PDT, Outcome 1 Mean reduction in lesion counts.
Comparison 60 Trichloroacetic acid peel versus 5% 5‐FU, Outcome 1 Mean percentage of reduction in lesions.
Comparison 61 Cryotherapy versus cryotherapy with betulin‐based oleogel, Outcome 1 Participant complete clearance.
Comparison 61 Cryotherapy versus cryotherapy with betulin‐based oleogel, Outcome 2 Participant partial (>75%) clearance.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 1 Participant complete clearance at 6 months.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 2 Mean reduction in lesion counts at 6 months.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 3 Mean percentage of reduction in lesion counts at 6 months.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 4 Minor adverse events excluding skin irritation: body as a whole: allergic reaction.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 5 Minor adverse events excluding skin irritation: dermatology: hyperesthesia.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 6 Minor adverse events excluding skin irritation: dermatology: skin discoloration.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 7 Minor adverse events excluding skin irritation: dermatology: vesiculobullous rash.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 8 Minor adverse events excluding skin irritation: digestive: cheilitis.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 9 Minor adverse events excluding skin irritation: special senses: conjunctivitis.
Comparison 62 (0.5% 5‐FU + cryotherapy) versus (vehicle + cryotherapy), Outcome 10 Minor adverse events excluding skin irritation: special senses: eye irritation.
Comparison 63 (vehicle + cryotherapy) versus (0.5% 5‐FU + cryotherapy), Outcome 1 Participant complete clearance at 6 months.
Comparison 63 (vehicle + cryotherapy) versus (0.5% 5‐FU + cryotherapy), Outcome 2 Mean reduction in lesion counts at 6 months.
Comparison 63 (vehicle + cryotherapy) versus (0.5% 5‐FU + cryotherapy), Outcome 3 Mean percentage of reduction in lesion counts at 6 months.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 1 Participant complete clearance of all lesions.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 2 Participant complete clearance of target (cryotherapy treated) lesions.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 3 Participant complete clearance of subclinical lesions.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 4 Mean percentage of reduction in all lesion counts.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 5 Mean percentage of reduction in target (cryotherapy treated) lesion counts.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 6 Withdrawal due to adverse events.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 7 Skin irritation.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 8 Minor adverse events excluding skin irritation: body as a whole: fatigue.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 9 Minor adverse events excluding skin irritation: digestive: nausea.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 10 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 11 Minor adverse events excluding skin irritation: respiratory: upper respiratory tract infection.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 12 Minor adverse events excluding skin irritation: respiratory: bronchitis.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 13 Minor adverse events excluding skin irritation: respiratory: sinusitis.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 14 Minor adverse events excluding skin irritation: special senses: conjunctivitis.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 15 Cosmetic outcomes: Improved global photoageing score.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 16 Cosmetic outcomes: Improved fine lines.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 17 Cosmetic outcomes: Improved tactile roughness.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 18 Cosmetic outcomes: Improved mottled pigmentation.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 19 Cosmetic outcomes: Improved sallowness.
Comparison 64 Cryotherapy with vehicle versus cryotherapy with imiquimod, Outcome 20 Cosmetic outcomes: cosmetic appearance score.
Comparison 65 Cryotherapy with imiquimod versus cryotherapy with vehicle, Outcome 1 Participant complete clearance of all lesions.
Comparison 65 Cryotherapy with imiquimod versus cryotherapy with vehicle, Outcome 2 Mean percentage of reduction in all lesion counts.
Comparison 65 Cryotherapy with imiquimod versus cryotherapy with vehicle, Outcome 3 Withdrawal due to adverse events.
Comparison 65 Cryotherapy with imiquimod versus cryotherapy with vehicle, Outcome 4 Skin irritation.
| Study | Intervention | Patient | Investigator |
| Van der Geer 2009 | Diclofenac in 2.5% hyaluronic acid + ALA‐PDT | 3.3 | 3.4 |
| Van der Geer 2009 | 2.5% hyaluronic acid + ALA‐PDT | 2.4 | 2.7 |
Comparison 66 (3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT) versus (2.5% hyaluronic acid + ALA‐red light PDT), Outcome 1 Global Improvement Indices (‐2 to 4) at 6 months.
| Study | Intervention | At 6 weeks | At 6 months | At 12 months |
| Van der Geer 2009 | Diclofenac in 2.5% hyaluronic acid + ALA‐PDT | 10.13 | 11.56 | 12.5 |
| Van der Geer 2009 | 2.5% hyaluronic acid + ALA‐PDT | 9.9 | 10.56 | 8.8 |
Comparison 66 (3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT) versus (2.5% hyaluronic acid + ALA‐red light PDT), Outcome 2 Mean reduction of lesion counts.
| Diclofenac in 2.5% hyaluronic acid compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk With comparator | Corresponding risk With intervention | |||||
| Participant complete clearance | ||||||
| 3% diclofenac in 2.5% hyaluronic acid/2.5% hyaluronic acid | Study population | RR 2.46 | 420 | ⊕⊕⊕⊝ | For all lesions, data from 30, 60, and 90 day treatments pooled together, assessment at 30 days after the end of treatment (Analysis 6.5) | |
| 127 per 1000 | 313 per 1000 | |||||
| Moderate | ||||||
| 132 per 1000 | 325 per 1000 | |||||
| 3% diclofenac in 2.5% hyaluronic acid/5% imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT/2.5% hyaluronic acid + ALA‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean reduction in lesion counts | ||||||
| 3% diclofenac in 2.5% hyaluronic acid/2.5% hyaluronic acid | The mean reduction in lesion counts in the control groups was | The mean reduction of lesion counts in the intervention groups was | ‐ | 345 | ⊕⊕⊕⊕ | Data from 30, 60, and 90 day treatments pooled together, assessment 30 days after the end of treatment (Analysis 6.12) |
| 3% diclofenac in 2.5% hyaluronic acid/ 5% imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT/2.5% hyaluronic acid + ALA‐red light PDT | See comment | See comment | Not estimable | 10 | ⊕⊕⊝⊝ | Intraindividual study: at 6 weeks; diclofenac/hyaluronic acid (HA) + ALA‐PDT = 10.13, HA + ALA‐PDT= 9.9, at 6 months; diclofenac/HA + ALA‐PDT = 11.56, HA + ALA‐PDT = 10.56, at 12 months; diclofenac/HA + ALA‐PDT = 12.5, HA + ALA‐PDT = 8.8 |
| Mean percentage of reduction in lesion counts | ||||||
| All comparisons | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Withdrawal due to adverse events | ||||||
| 3% diclofenac in 2.5% hyaluronic acid/2.5% hyaluronic acid | Study population | RR 3.59 | 592 | ⊕⊕⊕⊕ | Additional data from intraindividual study: no participant withdrew because of adverse events (N = 20). GRADE = low. | |
| 40 per 1000 | 144 per 1000 | |||||
| Moderate | ||||||
| 43 per 1000 | 154 per 1000 | |||||
| 3% diclofenac in 2.5% hyaluronic acid/5% imiquimod | 0 per 1000 | 0 per 1000 | Not estimable | 49 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT/2.5% hyaluronic acid + ALA‐red light PDT | 0 per 1000 | 0 per 1000 | Not estimable | 10 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Skin irritation | ||||||
| 3% diclofenac in 2.5% hyaluronic acid/2.5% hyaluronic acid | See comment | See comment | Not estimable | 20 | ⊕⊕⊝⊝ | Intraindividual study reported irritation only on the diclofenac treated side of 8 out of 20 participants |
| 3% diclofenac in 2.5% hyaluronic acid/5% imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid + ALA‐red light PDT/2.5% hyaluronic acid + ALA‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5‐fluorouracil (5‐FU) compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk With comparator | Corresponding risk With intervention | |||||
| Participant complete clearance | ||||||
| 0.5% 5‐FU/Vehicle | Study population | RR 8.86 | 522 | ⊕⊕⊕⊕ | Data from 1, 2, and 4 week treatments were pooled together (Analysis 9.1) | |
| 15 per 1000 | 136 per 1000 | |||||
| Moderate | ||||||
| 0 per 1000 | 0 per 1000 | |||||
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | 71 per 1000 | 291 per 1000 | RR 4.08 | 142 | ⊕⊕⊝⊝ | 1 cycle (Analysis 62.1) |
| 0.5% 5‐FU/ALA‐PDT | 292 per 1000 | 499 per 1000 | RR 1.71 | 48 | ⊕⊝⊝⊝ | Data from blue light and pulsed dye laser were pooled |
| 0.5% 5‐FU/5.0% 5‐FU | See comment | See comment | Not estimable | 21 | ⊕⊝⊝⊝ | Intraindividual study: 0.5% and 5.0% 5‐FU = 9/21 |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU /10% masoprocol | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/5% Imiquimod | Study population | RR 1.85 | 89 | ⊕⊝⊝⊝ | ||
| 600 per 1000 | 1000 per 1000 | |||||
| Moderate | ||||||
| 555 per 1000 | 1000 per 1000 | |||||
| 5% 5‐FU/Carbon dioxide laser resurfacing | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Er:YAG laser resurfacing | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Cryotherapy | 680 per 1000 | 959 per 1000 | RR 1.41 | 49 | ⊕⊕⊝⊝ | Only data after the treatment |
| 5% 5‐FU/Trichloroacetic acid peel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean reduction in lesion counts | ||||||
| 0.5% 5‐FU/Vehicle | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | Data from 1, 2, and 4 week treatment were pooled. (Analysis 9.2) Results from another study (N = 177) with no SD: placebo: 2.7 lesions, 5‐FU = 8.8 lesions, GRADE = moderate |
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | 142 | ⊕⊕⊕⊝ | 1 cycle (Analysis 62.2) | |
| 0.5% 5‐FU/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5% 5‐FU/5.0% 5‐FU | See comment | See comment | Not estimable | 21 | ⊕⊕⊝⊝ | Intraindividual study: results with no SD: 0.5% 5‐FU = 8.8 lesions, 5.0% 5‐FU = 6.1 lesions |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | ‐ | 19 | ⊕⊕⊝⊝ | |
| 5% 5‐FU /10% masoprocol | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | ‐ | 49 | ⊕⊕⊝⊝ | |
| 5% 5‐FU/5% Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Carbon dioxide laser resurfacing | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Er:YAG laser resurfacing | See comment | See comment | Not estimable | 55 | ⊕⊕⊝⊝ | Results with no SD: number of lesions at 3 months:5‐FU = 13.2, resurfacing = 13.8, at 6 months:5‐FU = 12.5, resurfacing = 13.9, at 12 months: 5‐FU = 12.4, resurfacing = 14.2 |
| 5% 5‐FU/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Trichloroacetic acid peel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean percentage of reduction in lesion counts | ||||||
| 0.5% 5‐FU/Vehicle | The mean percentage of reduction in lesion counts ranged across control groups from | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | Data from 1 week treatment.(Analysis 9.3) Results from two other studies with no SD 1) (N = 207) placebo = 21.6%, 5‐FU = 69.5%, GRADE = low, 2)(N = 177) placebo = 34.4%, 5‐FU = 78.5%, GRADE = moderate |
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | |
| 0.5% 5‐FU/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5% 5‐FU/5.0% 5‐FU | See comment | See comment | Not estimable | 21 | ⊕⊕⊝⊝ | Intraindividual study: results with no SD: 0.5% 5‐FU = 67% and 5.0% 5‐FU = 47% |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU /10% masoprocol | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 49 | ⊕⊕⊕⊝ | |
| 5% 5‐FU/5% Imiquimod | See comment | See comment | Not estimable | 39 | ⊕⊕⊝⊝ | Results with no SD: 5% 5‐FU = 94%, 5% imiquimod = 66% |
| 5% 5‐FU/Carbon dioxide laser resurfacing | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 14 | ⊕⊝⊝⊝ | |
| 5% 5‐FU/Er:YAG laser resurfacing | See comment | See comment | Not estimable | 55 | ⊕⊕⊝⊝ | Results with no SD: at 6 months: 5‐FU = 79.2%, resurfacing 94.5%, at 12 months: 5‐FU = 76.6%, resurfacing = 91.1% |
| 5% 5‐FU/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Trichloroacetic acid peel | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 18 | ⊕⊝⊝⊝ | |
| Withdrawal due to adverse events | ||||||
| 0.5% 5‐FU/Vehicle | 0 per 1000 | N/A (5/119 = 42/1000) | RR 5.41 | 177 | ⊕⊝⊝⊝ | Data from 1, 2, and 4 week treatments were pooled.(Analysis 9.4) Another study reported 24/207 participants withdrew because of adverse events and 12 of them were in 4 week 5‐FU group. GRADE = low |
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | See comment | See comment | Not estimable | 142 | ⊕⊕⊝⊝ | There were no participant withdrawals in the first part of this three part study (incomplete data were given for the whole study). |
| 0.5% 5‐FU/ALA‐PDT | 0 per 1000 | N/A (1/12 = 83/1000) | RR 5.77 | 36 | ⊕⊕⊝⊝ | Data from blue light and pulsed dye laser were pooled |
| 0.5% 5‐FU/5.0% 5‐FU | See comment | See comment | Not estimable | 21 | ⊕⊕⊝⊝ | Intraindividual study: 16/21 discontinued treatment but did not withdraw: 4 because of 0.5%, 8 because of 5.0% , 4 because of both creams. |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | See comment | See comment | Not estimable | 19 | ⊕⊕⊝⊝ | Intraindividual study: 1 participant withdrew because of irritation but associated treatment was not specified. |
| 5% 5‐FU /10% masoprocol | 0 per 1000 | N/A (1/30 = 33/1000) | RR 2.71 | 57 | ⊕⊕⊝⊝ | |
| 5% 5‐FU/5% Imiquimod | 0 per 1000 | 0 per 1000 | Not estimable | 89 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| 5% 5‐FU/Carbon dioxide laser resurfacing | 250 per 1000 | 45 per 1000 | RR 0.18 | 17 | ⊕⊕⊝⊝ | |
| 5% 5‐FU/Er:YAG laser resurfacing | 0 per 1000 | N/A (1/27 = 37/1000) | RR 3.11 | 55 | ⊕⊕⊝⊝ | |
| 5% 5‐FU/Cryotherapy | 0 per 1000 | 0 per 1000 | Not estimable | 49 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 5% 5‐FU/Trichloroacetic acid peel | 0 per 1000 | 0 per 1000 | Not estimable | 18 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| Skin irritation | ||||||
| 0.5% 5‐FU/Vehicle | 654 per 1000 | 948 per 1000 | RR 1.45 | 384 | ⊕⊕⊕⊝ | Data from 1, 2, and 4 week treatments were pooled |
| 0.5% 5‐FU with cryotherapy/Vehicle with cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5% 5‐FU/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5% 5‐FU/5.0% 5‐FU | 1000 per 1000 | 1000 per 1000 | ‐ | 21 | ⊕⊕⊕⊝ | Intraindividual study: All participants reported facial irritation in association with both creams |
| 5% 5‐FU with 0.05% tretinoin /5% 5‐FU with placebo | See comment | See comment | Not estimable | 19 | ⊕⊕⊕⊝ | Intraindividual study: 12 had more irritation with tretinoin, 4 had more with placebo, and 3 had equal irritation. |
| 5% 5‐FU /10% masoprocol | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/5% Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Carbon dioxide laser resurfacing | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Er:YAG laser resurfacing | 429 per 1000 | 703 per 1000 | RR 1.64 | 55 | ⊕⊕⊝⊝ | At the end of treatment |
| 5% 5‐FU/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% 5‐FU/Trichloroacetic acid peel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Photodynamic therapy compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk With comparator | Corresponding risk With intervention | |||||
| Participant complete clearance | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | 83 per 1000 | 500 per 1000 | RR 6 | 24 | ⊕⊝⊝⊝ | |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | 500 per 1000 | 500 per 1000 (225 to 1000) | RR 1 | 24 | ⊕⊝⊝⊝ | |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | 97 per 1000 | 602 per 1000 | RR 6.22 | 243 | ⊕⊝⊝⊝ | 1 treatment. (Analysis 47.1) Additional intraindividual study: ALA‐PDT: 16/35, placebo‐PDT = 2/35. GRADE = moderate |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | 500 per 1000 | 85 per 1000 | RR 0.17 | 24 | ⊕⊝⊝⊝ | |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | 474 per 1000 | 237 per 1000 | RR 0.5 | 72 | ⊕⊕⊝⊝ | Data from assessment at 8 weeks after the end of treatment (Analysis 49.2) |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | 471 per 1000 | 235 per 1000 | RR 0.5 | 68 | ⊕⊝⊝⊝ | Data from assessment at 8 weeks after the end of treatment |
| 0.5h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | 735 per 1000 | 235 per 1000 | RR 0.32 | 68 | ⊕⊕⊝⊝ | Data from assessment at 8 weeks after the end of treatment |
| 1h ALA‐red light PDT /2h ALA‐red light PDT (individual lesions) | 471 per 1000 | 475 per 1000 | RR 1.01 | 72 | ⊕⊝⊝⊝ | Data from assessment at 8 weeks after the end of treatment |
| 1h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | 735 per 1000 | 471 per 1000 | RR 0.64 | 72 | ⊕⊕⊝⊝ | Data from assessment at 8 weeks after the end of treatment |
| 2h ALA‐red light PDT/4h ALA‐red light PDT (individual lesions) | 735 per 1000 | 471 per 1000 | RR 0.64 | 68 | ⊕⊕⊝⊝ | Data from assessment at 8 weeks after the end of treatment (Analysis 49.2) |
| 3‐4h ALA‐red light PDT/3 to 4h placebo‐red light PDT (individual lesions) | 89 per 1000 | 527 per 1000 | RR 5.94 | 422 | ⊕⊕⊕⊕ | 1 treatment (Analysis 47.1) |
| 3% diclofenac in 2.5% hyaluronan gel + 4h ALA‐red light PDT /2.5% hyaluronan gel + 4h ALA‐red light PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 4h ALA‐red light PDT/Cryotherapy (individual lesions) | 443 per 1000 | 580 per 1000 | RR 1.31 | 297 | ⊕⊕⊝⊝ | |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Intraindividual study: ALA‐PDT + 5% imiquimod = 2/25; ALA‐PDT + placebo = 2/25 |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 16 | ⊕⊕⊕⊝ | Intraindividual study: ALA‐PDT = 6/16, MAL‐PDT = 7/16 |
| MAL‐PDT | ||||||
| All day 16% MAL‐daylight PDT /All day 8% MAL‐daylight PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2h MAL‐daylight PDT /3h MAL‐daylight PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2.5‐4h MAL‐red light PDT /2.5‐4h placebo‐red light PDT (individual lesions) | 147 per 1000 | 656 per 1000 | RR 4.46 | 482 | ⊕⊕⊕⊝ | |
| 3h MAL‐red light LED PDT /3h MAL‐broad visible + water‐filtered infrared A PDT (individual lesions) | 500 per 1000 | 575 per 1000 | RR 1.15 | 80 | ⊕⊕⊝⊝ | Data from assessment at 12 weeks after the end of treatment.(Analysis 53.1) |
| 3h MAL‐red light LED PDT /3h MAL‐daylight PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Single 3h MAL‐red light PDT /Multiple 3h MAL‐red light PDT [2 treatments 1 week apart] (individual lesions) | 755 per 1000 | 883 per 1000 | RR 1.17 | 211 | ⊕⊕⊝⊝ | |
| 3h MAL‐red light PDT /Cryotherapy (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean reduction in lesion counts | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT /2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3‐4h ALA‐red light PDT /3‐4h placebo‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid gel + 4h ALA‐red light PDT /2.5% hyaluronic acid gel + 4h ALA‐red light PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 10 | ⊕⊕⊝⊝ | Intraindividual study: at 6 weeks; diclofenac/hyaluronic acid (HA) + ALA‐PDT = 10.13, HA + ALA‐PDT= 9.9, at 6 months:; diclofenac/HA + ALA‐PDT = 11.56, HA + ALA‐PDT = 10.56, at 12 months; diclofenac/HA + ALA‐PDT = 12.5, HA + ALA‐PDT = 8.8 |
| 4h ALA‐red light PDT /Cryotherapy (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Results from intraindividual study without SD: ALA‐PDT + 5% imiquimod = 19.9 lesions; ALA‐PDT + placebo = 16.0 lesions |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 0.6 higher | ‐ | 15 | ⊕⊕⊝⊝ | |
| MAL‐PDT | ||||||
| All day 16% MAL‐daylight PDT /All day 8% MAL‐daylight PDT (field‐directedtreatments) | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 0.3 higher | ‐ | 29 | ⊕⊕⊝⊝ | |
| 2h MAL‐daylight PDT /3h MAL‐daylight PDT (field‐directedtreatments) | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 0.1 higher | 120 | ⊕⊕⊝⊝ | ||
| 2.5‐4h MAL‐red light PDT /2.5‐4h placebo‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light LED PDT /3h MAL‐broad visible + water‐filtered infrared A PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light LED PDT /3h MAL‐daylight PDT (field‐directedtreatments) | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 0.4 lower | ‐ | 29 | ⊕⊕⊝⊝ | |
| Single 3h MAL‐red light PDT /Multiple 3h MAL‐red light PDT [2 treatments 1 week apart] (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light PDT /Cryotherapy (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean percentage of reduction in lesion count | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT /2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3‐4h ALA‐red light PDT /3‐4h placebo‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3% diclofenac in 2.5% hyaluronic acid gel + 4h ALA‐red light PDT /2.5% hyaluronic acid gel + 4h ALA‐red light PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 4h ALA‐red light PDT /Cryotherapy (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Results from intraindividual study without SD: ALA‐PDT + 5% imiquimod = 86.7%; ALA‐PDT + placebo = 73.1% |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | ‐ | See comment | ‐ | ‐ | ‐ | Not reported |
| MAL‐PDT | ||||||
| All day 16% MAL‐daylight PDT /All day 8% MAL‐daylight PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 29 | ⊕⊕⊝⊝ | Data with no SD: 16% MAL‐daylight PDT = 76.9%, 8% MAL‐daylight PDT = 79.5%. |
| 2h MAL‐daylight PDT /3h MAL‐daylight PDT (field‐directedtreatments) | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was 2.6 higher | ‐ | 120 | ⊕⊕⊝⊝ | |
| 2.5‐4h MAL‐red light PDT /2.5‐4h placebo‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light LED PDT /3h MAL‐broad visible + water‐filtered infrared A PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light LED PDT /3h MAL‐daylight PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 29 | ⊕⊕⊝⊝ | Data with no SD: MAL‐red light LED PDT = 71%, MAL‐daylight PDT = 79%. |
| Single 3h MAL‐red light PDT /Multiple 3h MAL‐red light PDT [2 treatments 1 week apart] (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3h MAL‐red light PDT /Cryotherapy (individual lesions) | See comment | See comment | Not estimable | 240 | ⊕⊝⊝⊝ | Intraindividual studies with no SD: at 12 weeks: MAL‐PDT = 84.4%, cryotherapy = 74.5%, at 24 weeks: MAL‐PDT = 75‐86.7%, cryotherapy = 83.9‐87% |
| Withdrawal due to adverse events | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 24 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | 83 per 1000 | 28 per 1000 | RR 0.33 | 24 | ⊕⊕⊝⊝ | |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | 0 per 1000 | 0 per 1000 | Not estimable | 271 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | 83 per 1000 | 28 per 1000 | RR 0.33 | 24 | ⊕⊕⊝⊝ | |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 72 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 68 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 0.5h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 68 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 1h ALA‐red light PDT /2h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 72 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 1h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 72 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 2h ALA‐red light PDT /4h ALA‐red light PDT (individual lesions) | See comment | See comment | Not estimable | 68 | ⊕⊝⊝⊝ | No details were given for the reasons for withdrawal. |
| 3‐4h ALA‐red light PDT /3‐4h placebo‐red light PDT (individual lesions) | 0 per 1000 | 0 per 1000 | Not estimable | 391 | ⊕⊕⊕⊕ | There were no participant withdrawals due to adverse events. |
| 3% diclofenac in 2.5% hyaluronic acid gel + 4h ALA‐red light PDT /2.5% hyaluronic acid gel + 4h ALA‐red light PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 10 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 4h ALA‐red light PDT /Cryotherapy (individual lesions) | 0 per 1000 | 0 per 1000 | Not estimable | 255 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | 0 per 1000 | 0 per 1000 | Not estimable | 30 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 25 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 15 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| MAL‐PDT | ||||||
| All day 16% MAL‐daylight PDT /All day 8% MAL‐daylight PDT (field‐directedtreatments) | See comment | See comment | Not estimable | 29 | ⊕⊕⊕⊝ | One of 30 participants withdrew because of adverse events unrelated to treatments. |
| 2h MAL‐daylight PDT /3h MAL‐daylight PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 120 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 2.5‐4h MAL‐red light PDT /2.5‐4h placebo‐red light PDT (individual lesions) | 0 per 1000 | N/A (3/130 = 23/1000) | RR 2 | 191 | ⊕⊝⊝⊝ | Two additional studies with no participant withdrawals because of adverse events (N = 211). GRADE = low |
| 3h MAL‐red light LED PDT /3h MAL‐broad visible + water‐filtered infrared A PDT (individual lesions) | 0 per 1000 | 0 per 1000 | Not estimable | 78 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 3h MAL‐red light LED PDT /3h MAL‐daylight PDT (field‐directedtreatments) | 0 per 1000 | 0 per 1000 | Not estimable | 29 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Single 3h MAL‐red light PDT /Multiple 3h MAL‐red light PDT [2 treatments 1 week apart] (individual lesions) | 9 per 1000 | 3 per 1000 | RR 0.34 | 211 | ⊕⊕⊝⊝ | |
| 3h MAL‐red light PDT /Cryotherapy (individual lesions) | 11 per 1000 | 10 per 1000 | RR 0.94 | 379 | ⊕⊕⊕⊝ | Two additional intraindividual studies: 4 of 119 and 2 of 121 participants withdrew because of adverse events and one of them was related to MAL‐PDT. GRADE = low |
| Skin irritation | ||||||
| ALA‐PDT | ||||||
| 1h ALA‐blue light PDT /1h ALA‐pulsed dye laser PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐blue light PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 14‐18h ALA‐blue light PDT /14‐18h placebo‐blue light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐pulsed dye laser PDT /0.5% 5‐FU (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/1h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 0.5h ALA‐red light PDT/4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT/2h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 1h ALA‐red light PDT/4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 2h ALA‐red light PDT/4h ALA‐red light PDT (individual lesions) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3 to 4h ALA‐red light PDT /3 to 4h placebo‐red light PDT (individual lesions) | 0 per 1000 | N/A (77/217 = 355/1000) | RR 59.72 | 300 | ⊕⊕⊕⊝ | Data for ALA‐PDT was given separately for two studies but not for placebo. Data from assessment after treatment (Analysis 47.7) |
| 3% diclofenac in 2.5% hyaluronic acid gel + 4h ALA‐red light PDT /2.5% hyaluronic acid gel + 4h ALA‐red light PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 4h ALA‐red light PDT /Cryotherapy (individual lesions) | 101 per 1000 | 371 per 1000 | RR 3.69 | 297 | ⊕⊕⊝⊝ | Assessment one day after the treatment (Analysis 51.2) |
| ALA‐red light PDT (individual lesions)/5% imiquimod (field‐directedtreatment) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐blue light PDT + 5% imiquimod / ALA‐blue light PDT + placebo (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐PDT versus MAL‐PDT | ||||||
| 5h ALA‐red light PDT /3h MAL‐red light PDT (field‐directedtreatments) | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| MAL‐PDT | ||||||
| All comparisons | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/ Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| ‐ | With comparator | With intervention | ‐ | ‐ | ‐ | ‐ |
| Participant complete clearance | ||||||
| Cryotherapy /Betulin‐based oleogel | 643 per 1000 | 784 per 1000 | RR 1.22 | 28 | ⊕⊝⊝⊝ | |
| Cryotherapy/cryotherapy with betulin‐based oleogel | 714 per 1000 | 786 per 1000 | RR 1.1 | 28 | ⊕⊝⊝⊝ | |
| Cryotherapy/5% 5‐FU | 958 per 1000 | 680 per 1000 | RR 0.71 | 49 | ⊕⊕⊝⊝ | Assessment after treatment (Analysis 43.1) |
| Vehicle with cryotherapy/0.5% 5‐FU with cryotherapy | 292 per 1000 | 70 per 1000 | RR 0.24 | 142 | ⊕⊕⊝⊝ | 1 cycle (Analysis 63.1) |
| Cryotherapy /Imiquimod | 846 per 1000 | 677 per 1000 | RR 0.8 | 51 | ⊕⊝⊝⊝ | 5% imiquimod (Analysis 44.1) |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | Study population | RR 0.2 | 311 | ⊕⊕⊕⊕ | Pooled data (5% and 3.75% imiquimod)(Analysis 64.1) Results from an additional intraindividual study: cryotherapy + vehicle = 5/27, cryotherapy+imiquimod = 8/27 GRADE = moderate | |
| 287 per 1000 | 57 per 1000 | |||||
| Moderate | ||||||
| 264 per 1000 | 53 per 1000 | |||||
| Cryotherapy /ALA‐red light PDT | 581 per 1000 | 442 per 1000 | RR 0.76 | 297 | ⊕⊕⊝⊝ | |
| Cryotherapy/MAL‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean reduction in lesion counts | ||||||
| Cryotherapy /Betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/cryotherapy with betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Vehicle + cryotherapy/0.5% 5‐FU + cryotherapy | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | 1 cycle (Analysis 63.2) |
| Cryotherapy /Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy /ALA‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/MAL‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mean percentage of reduction in lesion counts | ||||||
| Cryotherapy /Betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/cryotherapy with betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Vehicle with cryotherapy/0.5% 5‐FU with cryotherapy | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was | ‐ | 142 | ⊕⊕⊕⊝ | |
| Cryotherapy /Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | See comment | See comment | ‐ | 301 | ⊕⊝⊝⊝ | High heterogeneity (I2=86%) between 3.75% (parallel group, MD ‐34.10, 95% CI ‐41.38 to ‐26.82)) and 5.0% (intraindividual, MD ‐11.20, 95% CI ‐26.53 to 4.13) imiquimod studies. (Analysis 64.4) |
| Cryotherapy /ALA‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/MAL‐red light PDT | See comment | See comment | Not estimable | 240 | ⊕⊝⊝⊝ | Intraindividual studies with no SD: at 12 weeks: cryotherapy = 74.5%, MAL‐PDT= 84.4%, at 24 weeks: cryotherapy = 83.9‐87%, MAL‐PDT = 75‐86.7% |
| Withdrawal due to adverse events | ||||||
| Cryotherapy /Betulin‐based oleogel | 0 per 1000 | 0 per 1000 | Not estimable | 28 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy/cryotherapy with betulin‐based oleogel | 0 per 1000 | 0 per 1000 | Not estimable | 28 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy/5% 5‐FU | 0 per 1000 | 0 per 1000 | Not estimable | 49 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Vehicle with cryotherapy/0.5% 5‐FU with cryotherapy | See comment | See comment | Not estimable | 142 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events in the first part of this three part study (incomplete data were given for the whole study). |
| Cryotherapy /Imiquimod | 0 per 1000 | 0 per 1000 | Not estimable | 51 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | Study population | RR 0.93 | 312 | ⊕⊕⊕⊝ | Pooled data (5% and 3.75% imiquimod) (Analysis 64.6) | |
| 33 per 1000 | 30 per 1000 | |||||
| Moderate | ||||||
| 21 per 1000 | 20 per 1000 | |||||
| Cryotherapy /ALA‐ red light PDT | 0 per 1000 | 0 per 1000 | Not estimable | 297 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy/MAL‐ red light PDT | 11 per 1000 | 11 per 1000 | RR 1.06 | 379 | ⊕⊕⊕⊝ | Two additional intraindividual studies: 4 of 119 and 2 of 121 participants withdrew because of adverse events and one of them was related to MAL‐PDT. GRADE = low |
| Skin irritation | ||||||
| Cryotherapy /Betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/cryotherapy with betulin‐based oleogel | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy/5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Vehicle with cryotherapy/0.5% 5‐FU with cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy /Imiquimod | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy with vehicle /Cryotherapy with imiquimod | Study population | RR 0.39 | 311 | ⊕⊕⊕⊝ | Pooled data (5% and 3.75% imiquimod) | |
| 83 per 1000 | 32 per 1000 | |||||
| Moderate | ||||||
| 125 per 1000 | 49 per 1000 | |||||
| Cryotherapy /ALA‐red light PDT | 372 per 1000 | 100 per 1000 | RR 0.27 | 297 | ⊕⊕⊝⊝ | Assessment one day after the treatment (Analysis 46.2) |
| Cryotherapy/MAL‐red light PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Imiquimod compared to interventions for actinic keratoses in immunocompetent participants | ||||||
| Intervention/Comparison intervention | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| ‐ | With comparator | With intervention | ‐ | ‐ | ‐ | ‐ |
| Participant complete clearance | ||||||
| 2.5% imiquimod/placebo | 62 per 1000 | 277 per 1000 | RR 4.49 | 486 | ⊕⊕⊕⊕ | |
| 3.75% imiquimod/placebo | Study population | RR 6.45 | 730 | ⊕⊕⊕⊕ | ||
| 53 per 1000 | 343 per 1000 | |||||
| Moderate | ||||||
| 50 per 1000 | 322 per 1000 | |||||
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | 33 per 1000 | 301 per 1000 | RR 9.12 | 247 | ⊕⊕⊕⊝ | For all lesions |
| 5% imiquimod/placebo | Study population | RR 7.70 | 1871 | ⊕⊕⊕⊕ | ||
| 48 per 1000 | 371 per 1000 | |||||
| Moderate | ||||||
| 32 per 1000 | 246 per 1000 | |||||
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod /5% 5‐FU | See comment | See comment | ‐ | 89 | ⊕⊝⊝⊝ | The two studies was associated with high heterogeneity (I²= 93%) and the results could not be pooled together. One study favoured 5‐FU (RR 0.31, 95% CI 0.14 to 0.67] whereas the other did not (RR 0.88, 95% CI 0.73 to 1.06] (Analysis 22.1) |
| 5% imiquimod/Cryotherapy | 680 per 1000 | 843 per 1000 | RR 1.24 | 51 | ⊕⊝⊝⊝ | |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | 91 per 1000 | 225 per 1000 | RR 2.48 | 64 | ⊕⊕⊝⊝ | For all lesions.(Analysis 65.1) Results from an additional intraindividual study: cryotherapy + imiquimod side (8/27 = 30%), cryotherapy alone side (5/27 = 19%), GRADE = low |
| 5% imiquimod/ALA‐PDT | ‐ | Not reported | ||||
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Intraindividual study: ALA‐PDT + 5% imiquimod = 2/25; ALA‐PDT + placebo = 2/25 |
| Mean reduction in lesion counts | ||||||
| 2.5% imiquimod/placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3.75% imiquimod/placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/placebo | The mean reduction in lesion counts in the control groups was | The mean reduction in lesion counts in the intervention groups was 2.20 higher | ‐ | 12 | ⊕⊕⊝⊝ | Results from an additional intraindividual study with no SD (N = 21): 5% imiquimod: 3.9 lesions, placebo = 0.5 lesions, GRADE = very low |
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod /5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Results from intraindividual study without SD: ALA‐PDT + 5% imiquimod= 19.9 lesions; ALA‐PDT + placebo= 16.0 lesions |
| Mean percentage of reduction in lesion counts | ||||||
| 2.5% imiquimod/placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 3.75% imiquimod/placebo | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was 46.90 higher | ‐ | 247 | ⊕⊕⊕⊝ | |
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was 34.1 higher | ‐ | 247 | ⊕⊕⊕⊝ | For all lesions (Analysis 65.2) |
| 5% imiquimod/placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod /5% 5‐FU | See comment | See comment | Not estimable | 39 | ⊕⊕⊝⊝ | Results with no SD: 5% imiquimod = 66%, 5% 5‐FU = 94% |
| 5% imiquimod/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | The mean percentage of reduction in lesion counts in the control groups was | The mean percentage of reduction in lesion counts in the intervention groups was 11.2 higher | ‐ | 27 | ⊕⊕⊝⊝ | For all lesions.(Analysis 65.2) Results from an additional intraindividual study: cryotherapy‐5% imiquimod = 73.2+27.1%, cryotherapy + vehicle = 62.0+30.3%. GRADE = moderate |
| 5% imiquimod/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | See comment | See comment | Not estimable | 25 | ⊕⊕⊝⊝ | Results from intraindividual study without SD: ALA‐PDT + 5% imiquimod = 86.7% ; ALA‐PDT + placebo = 73.1 % |
| Withdrawal due to adverse events | ||||||
| 2.5% imiquimod/placebo | 19 per 1000 | 9 per 1000 | RR 0.5 | 486 | ⊕⊕⊕⊝ | |
| 3.75% imiquimod/placebo | 19 per 1000 | 17 per 1000 | RR 0.92 | 483 | ⊕⊕⊕⊝ | |
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | 32 per 1000 | 41 per 1000 | RR 1.3 | 247 | ⊕⊕⊝⊝ | |
| 5% imiquimod/placebo | Study population | RR 2.59 | 2290 | ⊕⊕⊕⊝ | (Analysis 20.5) Four small sample size studies with no participant withdrawal are not included in meta‐analysis: pooled data, imiquimod 0/79 and placebo 0/31. Additional two intraindividual studies: no participant withdrew because of adverse events (0/42) GRADE = very low (both studies had more than 20% participant lost). | |
| 21 per 1000 | 56 per 1000 | |||||
| Moderate | ||||||
| 5 per 1000 | 13 per 1000 | |||||
| High | ||||||
| 0 per 1000 | 0 per 1000 | |||||
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | 0 per 1000 | 0 per 1000 | Not estimable | 49 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 5% imiquimod /5% 5‐FU | 0 per 1000 | 0 per 1000 | Not estimable | 50 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| 5% imiquimod/Cryotherapy | 0 per 1000 | 0 per 1000 | Not estimable | 51 | ⊕⊕⊕⊝ | There were no participant withdrawals due to adverse events. |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | 30 per 1000 | 10 per 1000 | RR 0.34 | 65 | ⊕⊕⊝⊝ | |
| 5% imiquimod/ALA‐PDT | 0 per 1000 | 0 per 1000 | Not estimable | 30 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | 0 per 1000 | 0 per 1000 | Not estimable | 25 | ⊕⊕⊝⊝ | There were no participant withdrawals due to adverse events. |
| Skin irritation | ||||||
| 2.5% imiquimod/placebo | 6 per 1000 | 21 per 1000 | RR 3.45 | 486 | ⊕⊕⊕⊝ | |
| 3.75% imiquimod/placebo | 6 per 1000 | 30 per 1000 | RR 4.86 | 484 | ⊕⊕⊕⊝ | |
| Cryotherapy + 3.75% imiquimod/Cryotherapy + vehicle | 8 per 1000 | 56 per 1000 | RR 6.72 | 247 | ⊕⊕⊝⊝ | |
| 5% imiquimod/placebo | 5 per 1000 | 18 per 1000 | RR 3.68 | 708 | ⊕⊕⊕⊝ | Additional intraindividual study: similar mild irritation between the two treatment sides (N = 20) GRADE = very low |
| 5% imiquimod/3% diclofenac in 2.5% hyaluronic acid | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/5% 5‐FU | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| 5% imiquimod/Cryotherapy | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Cryotherapy + 5% imiquimod/Cryotherapy + vehicle | 121 per 1000 | 194 per 1000 | RR 1.6 | 64 | ⊕⊕⊝⊝ | |
| 5% imiquimod/ALA‐PDT | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| ALA‐PDT + 5% imiquimod/ALA‐PDT + placebo | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global Improvement Indices (investigator)‐cleared Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Mean changes in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2.1 0.1% adapalene gel | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 0.3% adapalene gel | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Minor adverse events excluding skin irritation: dermatitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global Improvement Indices (investigator)‐cleared Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Mean changes in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Minor adverse events excluding skin irritation: dermatitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage of reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean changes in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Cosmetic outcomes: Reduction in total cosmetic appearance score Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Mean reduction in lesion counts‐total Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3 Mean reduction in lesion counts‐per anatomical locations Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3.1 Face | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Scalp | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.3 Upper extremities | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Cosmetic outcomes: Number of participants with decreased infiltration and disappearance of crust Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Investigator Global Improvement Indices‐completely improved Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 30 day treatment/30 day follow‐up | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 4.0 [0.89, 17.89] |
| 1.2 60 day treatment/30 day follow‐up | 1 | 97 | Risk Ratio (M‐H, Random, 95% CI) | 3.06 [1.21, 7.77] |
| 1.3 90 day treatment/30 day follow‐up | 1 | 117 | Risk Ratio (M‐H, Random, 95% CI) | 2.50 [1.37, 4.55] |
| 2 Participant Global Improvement Indices‐completely improved Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 30 day treatment/30 day follow‐up | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 4.0 [0.89, 17.89] |
| 2.2 60 day treatment/30 day follow‐up | 1 | 97 | Risk Ratio (M‐H, Random, 95% CI) | 2.86 [1.12, 7.32] |
| 2.3 90 day treatment/30 day follow‐up | 1 | 117 | Risk Ratio (M‐H, Random, 95% CI) | 2.44 [1.28, 4.64] |
| 3 Participant complete clearance at end of treatment (>56 days) Show forest plot | 2 | 280 | Risk Ratio (M‐H, Random, 95% CI) | 1.95 [1.21, 3.13] |
| 4 Participant complete clearance (target lesions) Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.1 30 day treatment/ 30 day follow‐up | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 3.5 [0.76, 16.01] |
| 4.2 60 day treatment/ 30 day follow‐up | 1 | 97 | Risk Ratio (M‐H, Random, 95% CI) | 3.27 [1.30, 8.21] |
| 4.3 90 day treatment/ 30 day follow‐up | 2 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 2.87 [1.84, 4.48] |
| 5 Participant complete clearance (all lesions) Show forest plot | 3 | 420 | Risk Ratio (M‐H, Random, 95% CI) | 2.46 [1.66, 3.66] |
| 5.1 30 day treatment/ 30 day follow‐up | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 3.5 [0.76, 16.01] |
| 5.2 60 day treatment/ 30 day follow‐up | 1 | 97 | Risk Ratio (M‐H, Random, 95% CI) | 3.83 [1.37, 10.71] |
| 5.3 90 day treatment/30 day follow‐up | 2 | 225 | Risk Ratio (M‐H, Random, 95% CI) | 2.20 [1.40, 3.44] |
| 6 Participant complete clearance for 30 day treatment by locations Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.1 Scalp | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Forehead | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 Face | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.4 Back of hand | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Participant complete clearance for 60 day treatment by locations Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7.1 Scalp | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.2 Forehead | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.3 Face | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.4 Arm/forearm | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.5 Back of hand | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Participant complete clearance for 90 day treatment by locations Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 8.1 Scalp | 2 | 23 | Risk Ratio (M‐H, Random, 95% CI) | 1.24 [0.25, 6.08] |
| 8.2 Forehead | 2 | 95 | Risk Ratio (M‐H, Random, 95% CI) | 1.71 [1.03, 2.85] |
| 8.3 Face | 2 | 47 | Risk Ratio (M‐H, Random, 95% CI) | 2.15 [1.05, 4.40] |
| 8.4 Arm/forearm | 2 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 1.94 [0.26, 14.40] |
| 8.5 Back of hand | 2 | 63 | Risk Ratio (M‐H, Random, 95% CI) | 1.71 [0.04, 65.87] |
| 9 Participant complete clearance in immunosuppressed participants Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Participant partial (>75%) clearance in immunosuppressed participants Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11 Mean reduction of lesion counts (30‐90 days ): At the end of study Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 11.1 90 days | 1 | 150 | Mean Difference (IV, Random, 95% CI) | 0.80 [‐1.48, 3.08] |
| 12 Mean reduction of lesion counts (30‐90 days): 30 day follow‐up Show forest plot | 2 | 345 | Mean Difference (IV, Random, 95% CI) | 2.55 [1.56, 3.53] |
| 12.1 30 days | 1 | 98 | Mean Difference (IV, Random, 95% CI) | 2.00 [0.63, 3.37] |
| 12.2 60 days | 1 | 97 | Mean Difference (IV, Random, 95% CI) | 2.40 [0.73, 4.07] |
| 12.3 90 days | 1 | 150 | Mean Difference (IV, Random, 95% CI) | 3.80 [1.83, 5.77] |
| 13 Withdrawal due to adverse events Show forest plot | 4 | 592 | Risk Ratio (M‐H, Random, 95% CI) | 3.59 [1.92, 6.70] |
| 14 Minor adverse event: body as a whole : in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 15 Minor adverse event: body as a whole : "flu" Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 16 Minor adverse event:: body as a whole : infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 17 Minor adverse event: cardiovascular: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 18 Minor adverse event: cardiovascular: sinus bradycardia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 19 Minor adverse event: dermatological: bursitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 20 Minor adverse event: dermatological: dry skin Show forest plot | 3 | 462 | Risk Ratio (M‐H, Random, 95% CI) | 2.40 [1.20, 4.78] |
| 21 Minor adverse event: dermatological: herpes zoster Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 22 Minor adverse event: dermatological: rash vesiculobullous Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 23 Minor adverse event::dermatological: seborrhoea Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 24 Minor adverse event: dermatological: skin exfoliation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 25 Minor adverse event: dermatological: ulcerated skin Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 26 Minor adverse event: digestive : in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 27 Minor adverse event: hemic and lymphatic: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 28 Minor adverse event: metabolic and nutritional disorders : in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 29 Minor adverse event: musculoskeletal and connective tissue: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 30 Minor adverse event: musculoskeletal and connective tissue: hypokinesia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 31 Minor adverse event: nervous system: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 32 Minor adverse event: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 33 Minor adverse event: nervous system: hyperaesthesia Show forest plot | 2 | 345 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.30, 2.60] |
| 34 Minor adverse event: nervous system: paraesthesia Show forest plot | 2 | 345 | Risk Ratio (M‐H, Random, 95% CI) | 2.53 [0.57, 11.20] |
| 35 Minor adverse event: respiratory: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 36 Minor adverse event: respiratory: bronchitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 37 Minor adverse event: respiratory: pharyngitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 38 Minor adverse event: respiratory: upper respiratory tract infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 39 Minor adverse event: special senses: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 40 Minor adverse event: urogenital: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Investigator Global Improvement Indices‐Complete improvement Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Participant Global Improvement Indices‐Complete improvement Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction in lesions counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 3 | 522 | Risk Ratio (M‐H, Random, 95% CI) | 8.86 [3.67, 21.40] |
| 1.1 1 week treatment with 4 week follow‐up | 3 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 8.30 [2.04, 33.76] |
| 1.2 2 week treatment with 4 week follow‐up | 2 | 128 | Risk Ratio (M‐H, Random, 95% CI) | 6.42 [1.27, 32.59] |
| 1.3 4 week treatment with 4 week follow‐up | 2 | 127 | Risk Ratio (M‐H, Random, 95% CI) | 13.07 [2.68, 63.66] |
| 2 Mean reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3 Mean percentage of reduction in lesion counts Show forest plot | 1 | 142 | Mean Difference (IV, Random, 95% CI) | 33.60 [22.88, 44.32] |
| 4 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Skin irritation Show forest plot | 2 | 384 | Risk Ratio (M‐H, Random, 95% CI) | 1.45 [1.27, 1.65] |
| 6 Minor adverse event excluding skin irritation: body as a whole : in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7 Minor adverse event excluding skin irritation: body as a whole : allergy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8 Minor adverse event excluding skin irritation: body as a whole : "flu" or common cold Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Minor adverse event excluding skin irritation: musculoskeletal and connective tissue: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Minor adverse event excluding skin irritation: musculoskeletal and connective tissue: soreness Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11 Minor adverse event excluding skin irritation:nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12 Minor adverse event excluding skin irritation: respiratory: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13 Minor adverse event excluding skin irritation: respiratory: sinusitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 14 Minor adverse event excluding skin irritation: respiratory: upper respiratory tract infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 15 Minor adverse event excluding skin irritation: special senses: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 16 Minor adverse event excluding skin irritation:special senses: eye irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Daily for 1 week versus 4 weeks | 2 | 167 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.19, 0.81] |
| 1.2 Daily for 1 week versus 2 weeks | 2 | 169 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.23, 2.37] |
| 1.3 Daily for 2 weeks versus 4 weeks | 2 | 171 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.36, 0.87] |
| 2 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Skin irritation Show forest plot | 2 | 515 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.91, 1.00] |
| 3.1 Daily for 1 week versus 4 weeks | 2 | 170 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.89, 1.03] |
| 3.2 Daily for 1 week versus 2 weeks | 2 | 172 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.86, 1.08] |
| 3.3 Daily for 2 weeks versus 4 weeks | 2 | 173 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.88, 1.02] |
| 4 Minor adverse events excluding skin irritation: body as a whole : in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Minor adverse events excluding skin irritation: body as a whole : allergy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Minor adverse events excluding skin irritation: body as a whole : "flu" or common cold Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Minor adverse events excluding skin irritation: respiratory: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10 Minor adverse events excluding skin irritation: respiratory: sinusitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11 Minor adverse events excluding skin irritation: special senses: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12 Minor adverse events excluding skin irritation: special senses: eye irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12.1 Daily for 1 week versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.2 Daily for 1 week versus 2 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.3 Daily for 2 weeks versus 4 weeks | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Pulsed dye laser | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Combined | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Pulsed dye laser | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Combined | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 2 | 89 | Risk Ratio (M‐H, Random, 95% CI) | 1.85 [0.41, 8.33] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 After treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Investigator Global Improvement Indices ‐cleared Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Mean reduction of lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3 Mean percentage of reduction of lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 4 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage of reduction of lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Skin irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 At the end of treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 At 6 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage of reduction in lesions Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance‐number of doses Show forest plot | 11 | 2880 | Risk Ratio (M‐H, Random, 95% CI) | 6.91 [4.25, 11.26] |
| 1.1 9 or 18 doses (3 times/week for 3 weeks on, 4 weeks off) | 1 | 39 | Risk Ratio (M‐H, Random, 95% CI) | 2.76 [0.39, 19.40] |
| 1.2 12‐16 doses (2 times/week for 8 weeks or 3 times/week for 4 weeks) | 3 | 543 | Risk Ratio (M‐H, Random, 95% CI) | 7.88 [1.09, 56.67] |
| 1.3 12 or 24 doses (3 times/week for 4 weeks on , 4 weeks off, 4 weeks on) | 2 | 505 | Risk Ratio (M‐H, Random, 95% CI) | 8.81 [1.15, 67.32] |
| 1.4 24 doses (3 times/week for 8 weeks) | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 1.33 [0.07, 25.08] |
| 1.5 32‐36 doses (2 times/ week for 16 weeks or 3 times/ week for 12 weeks) | 4 | 888 | Risk Ratio (M‐H, Random, 95% CI) | 7.12 [3.06, 16.58] |
| 1.6 40 doses (5 times/week for 8 weeks) | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.03, 17.27] |
| 1.7 48 doses (3 times/ week for 16 weeks) | 3 | 795 | Risk Ratio (M‐H, Random, 95% CI) | 10.90 [3.59, 33.15] |
| 1.8 56 doses (7 times/week for 8 weeks) | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 1.29 [0.07, 24.29] |
| 2 Participant complete clearance in immunosuppressed participants Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Participant partial (>75%) clearance Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 9 or 18 doses (3 times/ week for 3 weeks on, 4 weeks off. 3 weeks on) | 1 | 39 | Risk Ratio (M‐H, Random, 95% CI) | 2.41 [0.91, 6.39] |
| 3.2 12‐16 doses (3 times/week for 4 weeks or 2 times/week for 8 weeks) | 2 | 284 | Risk Ratio (M‐H, Random, 95% CI) | 2.86 [1.53, 5.34] |
| 3.3 12 or 24 doses (3 times/week for 4 weeks on, 4 weeks off) | 2 | 505 | Risk Ratio (M‐H, Random, 95% CI) | 6.23 [0.70, 55.10] |
| 3.4 24 doses (3 times/week for 8 weeks) | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 4.0 [0.25, 62.85] |
| 3.5 32 doses (2 times/week for 16 weeks) | 1 | 436 | Risk Ratio (M‐H, Random, 95% CI) | 5.02 [3.44, 7.33] |
| 3.6 40 doses (5 times/week for 8 weeks) | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 3.35 [0.21, 53.51] |
| 3.7 48 doses (3 times/ week for 16 weeks) | 2 | 778 | Risk Ratio (M‐H, Random, 95% CI) | 8.46 [2.29, 31.16] |
| 3.8 56 doses (7 times/week for 8 weeks) | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 5.94 [0.39, 90.34] |
| 4 Participant partial (>75%) clearance in immunosuppressed participants Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Mean reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 6 Withdrawal due to adverse events Show forest plot | 8 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 6.1 12‐16 doses (2 times/week for 8 weeks or 3 times/week for 4 weeks) | 1 | 38 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.03, 16.74] |
| 6.2 12 or 24 doses (3 times/week for 4 weeks on , 4 weeks off, 4 weeks on) | 2 | 505 | Risk Ratio (M‐H, Random, 95% CI) | 1.60 [0.31, 8.23] |
| 6.3 24 doses (3 times/week for 8 weeks) | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 1.33 [0.07, 25.08] |
| 6.4 32‐36 doses (2 times/ week for 16 weeks or 3 times/ week for 12 weeks) | 3 | 858 | Risk Ratio (M‐H, Random, 95% CI) | 2.29 [0.80, 6.57] |
| 6.5 40 doses (5 times/week for 8 weeks) | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 4.90 [0.32, 75.60] |
| 6.6 48 doses (3 times/ week for 16 weeks) | 2 | 778 | Risk Ratio (M‐H, Random, 95% CI) | 2.69 [1.48, 4.90] |
| 6.7 56 doses (7 times/week for 8 weeks) | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 5.42 [0.35, 82.97] |
| 7 Withdrawal due to adverse events in immunosuppressed participants Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7.1 48 doses (3 times/ week for 16 weeks) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Minor adverse events excluding skin irritation: body as a whole: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8.1 12‐16 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.2 24‐28 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.3 40 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.4 56 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Minor adverse events excluding skin irritation: body as a whole: "flu" or "cold" Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9.1 12‐16 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9.2 24‐28 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9.3 40 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9.4 56 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10 Minor adverse events excluding skin irritation: digestive: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10.1 12‐16 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.2 24‐28 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.3 40 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.4 56 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11 Minor adverse events excluding skin irritation: digestive: nausea Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11.1 12‐16 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.2 24‐28 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.3 40 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.4 56 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12 Minor adverse events excluding skin irritation: nervous system: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12.1 12‐16 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.2 24‐28 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.3 40 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.4 56 doses | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 13 Cosmetic outcome: decrease in roughness/dryness/scaliness of the skin Show forest plot | 2 | 683 | Risk Ratio (M‐H, Random, 95% CI) | 3.23 [1.86, 5.58] |
| 13.1 32‐36 doses | 1 | 415 | Risk Ratio (M‐H, Random, 95% CI) | 2.54 [1.91, 3.37] |
| 13.2 48 doses | 1 | 268 | Risk Ratio (M‐H, Random, 95% CI) | 4.43 [2.69, 7.30] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 12 | 3087 | Risk Ratio (M‐H, Random, 95% CI) | 6.73 [5.03, 9.00] |
| 1.1 5.0% imiquimod | 9 | 1871 | Risk Ratio (M‐H, Random, 95% CI) | 7.70 [4.63, 12.79] |
| 1.2 3.75% imiquimod | 3 | 730 | Risk Ratio (M‐H, Random, 95% CI) | 6.45 [3.87, 10.73] |
| 1.3 2.5% imiquimod | 2 | 486 | Risk Ratio (M‐H, Random, 95% CI) | 4.49 [2.40, 8.39] |
| 2 Participant partial (>75%) clearance Show forest plot | 6 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 5.0% imiquimod | 4 | 1363 | Risk Ratio (M‐H, Random, 95% CI) | 6.71 [3.89, 11.57] |
| 2.2 3.75% imiquimod | 2 | 484 | Risk Ratio (M‐H, Random, 95% CI) | 3.11 [2.08, 4.66] |
| 2.3 2.5% imiquimod | 2 | 485 | Risk Ratio (M‐H, Random, 95% CI) | 2.48 [1.67, 3.68] |
| 3 Mean percentage of reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3.1 3.75% imiquimod | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Minor adverse events excluding skin irritation: body as a whole: 'flu" or "cold" Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 5.0% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.3 2.5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Withdrawal due to adverse events Show forest plot | 10 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 5.1 5.0% imiquimod | 8 | 2290 | Risk Ratio (M‐H, Random, 95% CI) | 2.59 [1.59, 4.23] |
| 5.2 3.75% imiquimod | 2 | 483 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.22, 3.93] |
| 5.3 2.5% imiquimod | 2 | 486 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.09, 2.70] |
| 6 Skin irritation Show forest plot | 5 | 1678 | Risk Ratio (M‐H, Random, 95% CI) | 3.93 [1.56, 9.88] |
| 6.1 5.0% imiquimod | 3 | 708 | Risk Ratio (M‐H, Random, 95% CI) | 3.68 [0.86, 15.74] |
| 6.2 3.75% imiquimod | 2 | 484 | Risk Ratio (M‐H, Random, 95% CI) | 4.86 [0.92, 25.83] |
| 6.3 2.5% imiquimod | 2 | 486 | Risk Ratio (M‐H, Random, 95% CI) | 3.45 [0.63, 18.97] |
| 7 Minor adverse events excluding skin irritation: body as a whole: pyrexia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7.1 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.2 2.5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Minor adverse events excluding skin irritation: hemic and lymphatic: lymphadenopathy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8.1 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.2 2.5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9.1 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10 Minor adverse events excluding skin irritation: nervous system: fatigue Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10.1 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.2 2.5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11.1 5.0% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.2 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.3 2.5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12 Minor adverse events excluding skin irritation: respiratory: cough Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12.1 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.2 2.5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 13 Minor adverse events excluding skin irritation: respiratory: sinusitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13.1 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 13.2 2.5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 14 Minor adverse events excluding skin irritation: respiratory: upper respiratory tract infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 14.1 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 14.2 2.5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 15 Minor adverse events excluding skin irritation: urogenital: urinary tract infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 15.1 3.75% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 15.2 2.5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 16 Cosmetic outcome: Participant's significantly or much improved cosmetic outcome assessed by investigator Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 16.1 3.75% imiquimod | 2 | 470 | Risk Ratio (M‐H, Random, 95% CI) | 2.71 [2.05, 3.58] |
| 16.2 2.5% imiquimod | 2 | 475 | Risk Ratio (M‐H, Random, 95% CI) | 2.25 [1.62, 3.14] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 12 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 2 times/week | 4 | 890 | Risk Ratio (M‐H, Random, 95% CI) | 5.36 [2.03, 14.16] |
| 1.2 3 times/week | 6 | 1336 | Risk Ratio (M‐H, Random, 95% CI) | 8.38 [3.79, 18.52] |
| 1.3 5 times/week | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.03, 17.27] |
| 1.4 7 times/week | 4 | 1253 | Risk Ratio (M‐H, Random, 95% CI) | 5.39 [3.65, 7.98] |
| 2 Participant partial (>75%) clearance Show forest plot | 6 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 2 times/week | 2 | 474 | Risk Ratio (M‐H, Random, 95% CI) | 4.99 [3.43, 7.26] |
| 2.2 3 times/week | 3 | 814 | Risk Ratio (M‐H, Random, 95% CI) | 7.65 [2.51, 23.32] |
| 2.3 5 times/week | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 3.35 [0.21, 53.51] |
| 2.4 7 times/week | 3 | 1006 | Risk Ratio (M‐H, Random, 95% CI) | 2.95 [1.99, 4.37] |
| 3 Withdrawal due to adverse events Show forest plot | 10 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 2 times/week | 4 | 896 | Risk Ratio (M‐H, Random, 95% CI) | 2.04 [0.75, 5.53] |
| 3.2 3 times/week | 5 | 1319 | Risk Ratio (M‐H, Random, 95% CI) | 2.47 [1.42, 4.30] |
| 3.3 5 times/week | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 4.90 [0.32, 75.60] |
| 3.4 7 times/week | 3 | 1006 | Risk Ratio (M‐H, Random, 95% CI) | 1.55 [0.33, 7.18] |
| 4 Minor adverse events excluding skin irritation:body as a whole: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 2 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 3 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.3 5 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.4 7 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Minor adverse events excluding skin irritation: body as a whole:"flu" or "cold" Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 5.1 2 times/week | 1 | 38 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.03, 16.74] |
| 5.2 3 times/week | 2 | 54 | Risk Ratio (M‐H, Random, 95% CI) | 2.67 [0.36, 19.83] |
| 5.3 5 times/week | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.03, 17.27] |
| 5.4 7 times/week | 2 | 527 | Risk Ratio (M‐H, Random, 95% CI) | 5.20 [0.28, 95.18] |
| 6 Minor adverse events excluding skin irritation: digestive: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.1 3 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 5 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 7 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Minor adverse events excluding skin irritation: digestive: nausea Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7.1 3 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.2 5 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.3 7 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Minor adverse events excluding skin irritation: nervous system: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8.1 3 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.2 7 times/week | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 9.1 3 times/week | 1 | 18 | Risk Ratio (M‐H, Random, 95% CI) | 3.77 [0.23, 63.05] |
| 9.2 5 times/week | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 1.81 [0.10, 31.53] |
| 9.3 7 times/week | 2 | 527 | Risk Ratio (M‐H, Random, 95% CI) | 4.48 [0.86, 23.31] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2 Cosmetic outcome: Investigator cosmetic outcome "excellent" Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Cosmetic outcome: normal skin surface Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance of target lesions Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Participant complete clearance of all lesions Show forest plot | 2 | 456 | Risk Ratio (M‐H, Random, 95% CI) | 4.50 [2.61, 7.74] |
| 3 Participant partial (>75%) clearance of target lesions Show forest plot | 2 | 280 | Risk Ratio (M‐H, Random, 95% CI) | 2.88 [1.81, 4.58] |
| 4 Cosmetic outcomes: changes in pigmentation Show forest plot | 3 | 514 | Risk Ratio (M‐H, Random, 95% CI) | 3.36 [0.63, 17.80] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance of target lesions Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 0.025% 3 days | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 0.05% 2‐3 days | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant complete clearance of all lesions Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 0.025% 3 days | 1 | 70 | Risk Ratio (M‐H, Random, 95% CI) | 4.0 [1.03, 15.55] |
| 2.2 0.05% 2‐3 days | 2 | 386 | Risk Ratio (M‐H, Random, 95% CI) | 5.14 [2.75, 9.62] |
| 3 Participant partial (>75%) clearance of target lesions Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 0.0025% 2 days | 1 | 19 | Risk Ratio (M‐H, Random, 95% CI) | 1.33 [0.21, 8.41] |
| 3.2 0.01% 2 days | 1 | 20 | Risk Ratio (M‐H, Random, 95% CI) | 0.5 [0.06, 4.23] |
| 3.3 0.025% 3 days | 1 | 70 | Risk Ratio (M‐H, Random, 95% CI) | 2.8 [1.13, 6.96] |
| 3.4 0.05% 2‐3 days | 2 | 171 | Risk Ratio (M‐H, Random, 95% CI) | 3.34 [1.84, 6.04] |
| 4 Cosmetic outcomes: changes in pigmentation Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.1 0.01% 2 days | 1 | 20 | Risk Ratio (M‐H, Random, 95% CI) | 1.47 [0.08, 25.88] |
| 4.2 0.05% 2 days | 2 | 253 | Risk Ratio (M‐H, Random, 95% CI) | 4.86 [0.48, 49.39] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance of target lesions Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 0.05% 2 days | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 0.05% 3 days | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant complete clearance of all lesions Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 0.05% 2 days | 2 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 4.32 [2.30, 8.11] |
| 2.2 0.05% 3 days | 1 | 87 | Risk Ratio (M‐H, Random, 95% CI) | 4.08 [1.59, 10.47] |
| 3 Participant partial (>75%) clearance of target lesions Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 0.05% 2 days | 2 | 104 | Risk Ratio (M‐H, Random, 95% CI) | 2.65 [1.41, 5.00] |
| 3.2 0.05% 3 days | 1 | 87 | Risk Ratio (M‐H, Random, 95% CI) | 3.23 [1.66, 6.29] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Investigator global improvement indices‐completely cleared Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Face | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Scalp | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Upper extremities | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Mean reduction of lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2.1 Face | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Scalp | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Upper extremities | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Skin irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Severe‐Skin irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global improvement indices‐cured Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Mean reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage of reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.1 At 3 months | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 At 6 months | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 After 1 cycle | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Minor adverse events excluding skin irritation: body as a whole: fatigue Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Minor adverse events excluding skin irritation: body as a whole: rigors Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Minor adverse events excluding skin irritation: nervous system: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11 Minor adverse events excluding skin irritation: nervous system: lethargy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 After 1 cycle | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Minor adverse events excluding skin irritation: body as a whole: fatigue Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Minor adverse events excluding skin irritation: body as a whole: rigors Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Minor adverse events excluding skin irritation: nervous system: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11 Minor adverse events excluding skin irritation: nervous system: lethargy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 After 1 cycle | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Minor adverse events excluding skin irritation: body as a whole: fatigue Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Minor adverse events excluding skin irritation: body as a whole: rigors Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Minor adverse events excluding skin irritation: nervous system: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11 Minor adverse events excluding skin irritation: nervous system: lethargy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 After 1 cycle | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Minor adverse events excluding skin irritation: body as a whole: fatigue Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Minor adverse events excluding skin irritation: body as a whole: rigors Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Minor adverse events excluding skin irritation: nervous system: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11 Minor adverse events excluding skin irritation: nervous system: lethargy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 After 1 cycle | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Minor adverse events excluding skin irritation: body as a whole: fatigue Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Minor adverse events excluding skin irritation: body as a whole: rigors Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Minor adverse events excluding skin irritation: nervous system: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11 Minor adverse events excluding skin irritation: nervous system: lethargy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13 Minor adverse events excluding skin irritation:skin and subcutaneous disorders: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 After 1 cycle | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 After 1 or 2 cycles | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Minor adverse events excluding skin irritation: body as a whole: fatigue Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Minor adverse events excluding skin irritation: body as a whole: rigors Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7 Minor adverse events excluding skin irritation:musculoskeletal and connective tissue: arthralgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Minor adverse events excluding skin irritation: nervous system: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11 Minor adverse events excluding skin irritation: nervous system: lethargy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12 Minor adverse events excluding skin irritation: nervous system: psychiatric disorders Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13 Minor adverse events excluding skin irritation: skin and subcutaneous disorders: in general Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean change in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction of lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage of reduction of lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage of reduction of lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction in lesion counts Show forest plot | Other data | No numeric data | ||
| 2 Mean percentage of reduction in lesion counts Show forest plot | Other data | No numeric data | ||
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Skin irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 At the end of treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.3 At 6 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Minor adverse events excluding skin irritation: dermatology: acne Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5.1 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 At 6 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.3 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Minor adverse events excluding skin irritation: dermatology:crustea Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.1 At the end of treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 At 6 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.4 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Minor adverse events excluding skin irritation: dermatology: infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7.1 At the end of treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Minor adverse events excluding skin irritation: dermatology: milia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8.1 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.2 At 6 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.3 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Minor adverse events excluding skin irritation: dermatology:pain Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9.1 At the end of treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9.2 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10 Cosmetic outcomes: changes in pigmentation (hypo) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10.1 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.2 At 6 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.3 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11 Cosmetic outcomes: scarring Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11.1 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.2 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12 Cosmetic outcomes: improvement in photoageing score Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12.1 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.2 At 6 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.3 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 After treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Cosmetic outcomes: excellent global cosmetic outcome Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Cosmetic outcomes: better skin appearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Cosmetic outcomes: excellent global cosmetic outcome Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Cosmetic outcomes: better skin appearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage of reduction in lesion counts Show forest plot | Other data | No numeric data | ||
| 2 Withdrawal due to adverse events Show forest plot | 2 | 379 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.16, 7.16] |
| 3 Cosmetic outcomes: excellent or good cosmetic outcomes by investigator Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4 Cosmetic outcomes: excellent or good cosmetic outcomes by participant Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Skin irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 During treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 One day after treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance [1 treatment] Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Blue light | 1 | 243 | Risk Ratio (M‐H, Random, 95% CI) | 6.22 [2.88, 13.43] |
| 1.2 Red light | 3 | 422 | Risk Ratio (M‐H, Random, 95% CI) | 5.94 [3.35, 10.54] |
| 2 Participant complete clearance [1 or 2 treatments] Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Red light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Participant complete clearance [1 or 2 treatments] by anatomical location Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 Face | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Scalp | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Participant partial (> 75%) clearance [1 treatment] Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Participant partial (>75%) clearance[1 or 2 treatments] Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Participant partial (>75%) clearance [1 or 2 treatment] by anatomical location Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.1 Face | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Scalp | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Skin irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7.1 Red light‐during illumination | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.2 Red light‐after treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Minor adverse events excluding skin irritation: body as a whole: injury Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Minor adverse events excluding skin irritation: cardiovascular: hypertension Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10 Minor adverse events excluding skin irritation: dermatology: skin discolouration Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10.1 Red light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11 Minor adverse events excluding skin irritation: dermatology: skin hypertrophy Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 12 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 13 Cosmetic outcome: very good or good general cosmetic outcome Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Cosmetic outcome: improvement in global response Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Cosmetic outcome: improvement in tactile roughness Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Cosmetic outcome: improvement in mottled hyperpigmentation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance at 4 weeks Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 0.5h versus 1.0h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 0.5h versus 2 h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 0.5h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.4 1h versus 2h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.5 1h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.6 2h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant complete clearance at 8 weeks Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 0.5h versus 1.0h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 0.5h versus 2 h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 0.5h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.4 1h versus 2h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.5 1h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.6 2h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Minor adverse events excluding skin irritation: metabolic and nutritional disorders: elevated alanine transaminase (ALT) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 0.5h versus 1.0h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 0.5h versus 2 h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.3 0.5h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Minor adverse events excluding skin irritation: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 0.5h versus 1h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 0.5h versus 2h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.3 0.5h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.4 1h versus 2h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.5 1h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.6 2h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Minor adverse events excluding skin irritation: other: epistaxis (nose bleeding) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5.1 0.5h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 1h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.3 2h versus 4h | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Pulsed dye laser | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Combined | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Pulsed dye laser | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Combined | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Pulsed dye laser | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.3 Combined | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Cosmetic outcome: improvement in global response Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 Pulsed dye laser | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.3 Combined | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Cosmetic outcome: improvement in tactile roughness Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 Pulsed dye laser | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.3 Combined | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Cosmetic outcome: improvement in mottled hyperpigmentation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.1 Blue light | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Pulsed dye laser | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 Combined | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Skin irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 During treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 One day after treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 5 | 482 | Risk Ratio (M‐H, Random, 95% CI) | 4.46 [3.17, 6.28] |
| 2 Participant partial (>75%) clearance Show forest plot | 2 | 191 | Risk Ratio (M‐H, Random, 95% CI) | 3.28 [1.73, 6.23] |
| 3 Withdrawal due to adverse events Show forest plot | 2 | 191 | Risk Ratio (M‐H, Random, 95% CI) | 2.00 [0.23, 17.74] |
| 4 Minor adverse event: nervous system: headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Cosmetic outcome: hyperpigmentation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 At 6 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 At 3 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 At 6 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 At 12 months | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Mean percentage of reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Withdrawal due to adverse events Show forest plot | 2 | 379 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.14, 6.36] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction in lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage of reduction in lesions Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Participant partial (>75%) clearance Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance at 6 months Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 1 cycle (1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 2 cycles ( 1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 3 cycles ( 1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Mean reduction in lesion counts at 6 months Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1 1 cycle (1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 2 cycles ( 1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 3 cycles ( 1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Mean percentage of reduction in lesion counts at 6 months Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1 1 cycle (1 week topical, cryosurgery at 4 weeks, follow‐up at 6 months) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Minor adverse events excluding skin irritation: body as a whole: allergic reaction Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Minor adverse events excluding skin irritation: dermatology: hyperesthesia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6 Minor adverse events excluding skin irritation: dermatology: skin discoloration Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7 Minor adverse events excluding skin irritation: dermatology: vesiculobullous rash Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 8 Minor adverse events excluding skin irritation: digestive: cheilitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Minor adverse events excluding skin irritation: special senses: conjunctivitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Minor adverse events excluding skin irritation: special senses: eye irritation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance at 6 months Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 1 cycle (1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 2 cycles ( 1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 3 cycles ( 1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Mean reduction in lesion counts at 6 months Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1 1 cycle (1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 2 cycles ( 1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 3 cycles ( 1 week topical, cryosurgery at week 4, follow‐up at 6 months) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Mean percentage of reduction in lesion counts at 6 months Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1 1 cycle (1 week topical, cryosurgery at 4 weeks, follow‐up at 6 months) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance of all lesions Show forest plot | 2 | 311 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.05, 0.73] |
| 1.1 5% imiquimod | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 0.40 [0.11, 1.42] |
| 1.2 3.75% imiquimod | 1 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 0.11 [0.04, 0.30] |
| 2 Participant complete clearance of target (cryotherapy treated) lesions Show forest plot | 2 | 311 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.36, 1.04] |
| 2.1 5% imiquimod | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.47, 1.60] |
| 2.2 3.75% imiquimod | 1 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.37, 0.68] |
| 3 Participant complete clearance of subclinical lesions Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 5% imiquimod | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Mean percentage of reduction in all lesion counts Show forest plot | 2 | 301 | Mean Difference (IV, Random, 95% CI) | ‐23.69 [‐46.03, ‐1.34] |
| 4.1 5% imquimod | 1 | 54 | Mean Difference (IV, Random, 95% CI) | ‐11.20 [‐26.53, 4.13] |
| 4.2 3.75% imiquimod | 1 | 247 | Mean Difference (IV, Random, 95% CI) | ‐34.10 [‐41.38, ‐26.82] |
| 5 Mean percentage of reduction in target (cryotherapy treated) lesion counts Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5.1 3.75% imiquimod | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Withdrawal due to adverse events Show forest plot | 2 | 312 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.28, 3.07] |
| 6.1 5% imiquimod | 1 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 68.95] |
| 6.2 3.75% imiquimod | 1 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.21, 2.79] |
| 7 Skin irritation Show forest plot | 2 | 311 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.10, 1.54] |
| 7.1 5% imiquimod | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.20, 2.01] |
| 7.2 3.75% imiquimod | 1 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 0.15 [0.02, 1.19] |
| 8 Minor adverse events excluding skin irritation: body as a whole: fatigue Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9 Minor adverse events excluding skin irritation: digestive: nausea Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10 Minor adverse events excluding skin irritation: musculoskeletal and connective tissue: myalgia Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11 Minor adverse events excluding skin irritation: respiratory: upper respiratory tract infection Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12 Minor adverse events excluding skin irritation: respiratory: bronchitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13 Minor adverse events excluding skin irritation: respiratory: sinusitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 14 Minor adverse events excluding skin irritation: special senses: conjunctivitis Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 15 Cosmetic outcomes: Improved global photoageing score Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 16 Cosmetic outcomes: Improved fine lines Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 17 Cosmetic outcomes: Improved tactile roughness Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 18 Cosmetic outcomes: Improved mottled pigmentation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 19 Cosmetic outcomes: Improved sallowness Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 20 Cosmetic outcomes: cosmetic appearance score Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 20.1 Investigator | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 20.2 Participant | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participant complete clearance of all lesions Show forest plot | 2 | 311 | Risk Ratio (M‐H, Random, 95% CI) | 5.04 [1.37, 18.51] |
| 1.1 5% imiquimod | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 2.48 [0.70, 8.76] |
| 1.2 3.75% imiquimod | 1 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 9.12 [3.36, 24.79] |
| 2 Mean percentage of reduction in all lesion counts Show forest plot | 2 | 301 | Mean Difference (IV, Random, 95% CI) | 23.69 [1.34, 46.03] |
| 2.1 5% imquimod | 1 | 54 | Mean Difference (IV, Random, 95% CI) | 11.20 [‐4.13, 26.53] |
| 2.2 3.75% imiquimod | 1 | 247 | Mean Difference (IV, Random, 95% CI) | 34.10 [26.82, 41.38] |
| 3 Withdrawal due to adverse events Show forest plot | 2 | 312 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.33, 3.56] |
| 3.1 5% imiquimod | 1 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 0.34 [0.01, 8.13] |
| 3.2 3.75% imiquimod | 1 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 1.30 [0.36, 4.73] |
| 4 Skin irritation Show forest plot | 2 | 311 | Risk Ratio (M‐H, Random, 95% CI) | 2.55 [0.65, 10.04] |
| 4.1 5% imiquimod | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.60 [0.50, 5.13] |
| 4.2 3.75% imiquimod | 1 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 6.72 [0.84, 53.83] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global Improvement Indices (‐2 to 4) at 6 months Show forest plot | Other data | No numeric data | ||
| 2 Mean reduction of lesion counts Show forest plot | Other data | No numeric data | ||
