Interventions for basal cell carcinoma of the skin.

BACKGROUND: Basal cell carcinoma (BCC) is the commonest cancer affecting white-skinned individuals, and worldwide incidence is increasing. Although rarely fatal, BCC is associated with significant morbidity and costs. First-line treatment is usually surgical excision, but alternatives are available. New published studies and the development of non-surgical treatments meant an update of our Cochrane Review (first published in 2003, and previously updated in 2007) was timely. OBJECTIVES: To assess the effects of interventions for BCC in immunocompetent adults. SEARCH METHODS: We updated our searches of the following databases to November 2019: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and LILACS. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions for BCC in immunocompetent adults with histologically-proven, primary BCC. Eligible comparators were placebo, active treatment, other treatments, or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcome measures were recurrence at three years and five years (measured clinically) (we included recurrence data outside of these time points if there was no measurement at three or five years) and participant- and observer-rated good/excellent cosmetic outcome. Secondary outcomes included pain during and after treatment, early treatment failure within six months, and adverse effects (AEs). We used GRADE to assess evidence certainty for each outcome. MAIN RESULTS: We included 52 RCTs (26 new) involving 6690 participants (median 89) in this update. All studies recruited from secondary care outpatient clinics. More males than females were included. Study duration ranged from six weeks to 10 years (average 13 months). Most studies (48/52) included only low-risk BCC (superficial (sBCC) and nodular (nBCC) histological subtypes). The majority of studies were at low or unclear risk of bias for most domains. Twenty-two studies were industry-funded: commercial sponsors conducted most of the studies assessing imiquimod, and just under half of the photodynamic therapy (PDT) studies. Overall, surgical interventions have the lowest recurrence rates. For high-risk facial BCC (high-risk histological subtype or located in the facial 'H-zone' or both), there may be slightly fewer recurrences with Mohs micrographic surgery (MMS) compared to surgical excision (SE) at three years (1.9% versus 2.9%, respectively) (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.16 to 2.64; 1 study, 331 participants; low-certainty evidence) and at five years (3.2% versus 5.2%, respectively) (RR 0.61, 95% CI 0.18 to 2.04; 1 study, 259 participants; low-certainty evidence). However, the 95% CI also includes the possibility of increased risk of recurrence and no difference between treatments. There may be little to no difference regarding improvement of cosmetic outcomes between MMS and SE, judged by participants and observers 18 months post-operatively (one study; low-certainty evidence); however, no raw data were available for this outcome. When comparing imiquimod and SE for nBCC or sBCC at low-risk sites, imiquimod probably results in more recurrences than SE at three years (16.4% versus 1.6%, respectively) (RR 10.30, 95% CI 3.22 to 32.94; 1 study, 401 participants; moderate-certainty evidence) and five years (17.5% versus 2.3%, respectively) (RR 7.73, 95% CI 2.81 to 21.3; 1 study, 383 participants; moderate-certainty evidence). There may be little to no difference in the number of participant-rated good/excellent cosmetic outcomes (RR 1.00, 95% CI 0.94 to 1.06; 1 study, 326 participants; low-certainty evidence). However, imiquimod may result in greater numbers of good/excellent cosmetic outcomes compared to SE when observer-rated (60.6% versus 35.6%, respectively) (RR 1.70, 95% CI 1.35 to 2.15; 1 study, 344 participants; low-certainty evidence). Both cosmetic outcomes were measured at three years. Based on one study of 347 participants with high- and low-risk primary BCC of the face, radiotherapy may result in more recurrences compared to SE under frozen section margin control at three years (5.2% versus 0%, respectively) (RR 19.11, 95% CI 1.12 to 325.78; low-certainty evidence) and at four years (6.4% versus 0.6%, respectively) (RR 11.06, 95% CI 1.44 to 84.77; low-certainty evidence). Radiotherapy probably results in a smaller number of good participant- (RR 0.76, 95% CI 0.63 to 0.91; 50.3% versus 66.1%, respectively) or observer-rated (RR 0.48, 95% CI 0.37 to 0.62; 28.9% versus 60.3%, respectively) good/excellent cosmetic outcomes compared to SE, when measured at four years, where dyspigmentation and telangiectasia can occur (both moderate-certainty evidence). Methyl-aminolevulinate (MAL)-PDT may result in more recurrences compared to SE at three years (36.4% versus 0%, respectively) (RR 26.47, 95% CI 1.63 to 429.92; 1 study; 68 participants with low-risk nBCC in the head and neck area; low-certainty evidence). There were no useable data for measurement at five years. MAL-PDT probably results in greater numbers of participant- (RR 1.18, 95% CI 1.09 to 1.27; 97.3% versus 82.5%) or observer-rated (RR 1.87, 95% CI 1.54 to 2.26; 87.1% versus 46.6%) good/excellent cosmetic outcomes at one year compared to SE (2 studies, 309 participants with low-risk nBCC and sBCC; moderate-certainty evidence). Based on moderate-certainty evidence (single low-risk sBCC), imiquimod probably results in fewer recurrences at three years compared to MAL-PDT (22.8% versus 51.6%, respectively) (RR 0.44, 95% CI 0.32 to 0.62; 277 participants) and five years (28.6% versus 68.6%, respectively) (RR 0.42, 95% CI 0.31 to 0.57; 228 participants). There is probably little to no difference in numbers of observer-rated good/excellent cosmetic outcomes at one year (RR 0.98, 95% CI 0.84 to 1.16; 370 participants). Participant-rated cosmetic outcomes were not measured for this comparison. AEs with surgical interventions include wound infections, graft necrosis and post-operative bleeding. Local AEs such as itching, weeping, pain and redness occur frequently with non-surgical interventions. Treatment-related AEs resulting in study modification or withdrawal occurred with imiquimod and MAL-PDT. AUTHORS' CONCLUSIONS: Surgical interventions have the lowest recurrence rates, and there may be slightly fewer recurrences with MMS over SE for high-risk facial primary BCC (low-certainty evidence). Non-surgical treatments, when used for low-risk BCC, are less effective than surgical treatments, but recurrence rates are acceptable and cosmetic outcomes are probably superior. Of the non-surgical treatments, imiquimod has the best evidence to support its efficacy. Overall, evidence certainty was low to moderate. Priorities for future research include core outcome measures and studies with longer-term follow-up.

Interventions for cutaneous Bowen's disease.

BACKGROUND: Bowen's disease is the clinical term for in situ squamous cell carcinoma of the skin. Cutaneous lesions present as largely asymptomatic, well-defined, scaly erythematous patches on sun-exposed skin. In general, people with Bowen's disease have an excellent prognosis because the disease is typically slow-growing and responds favourably to treatment. Lesions are persistent and can be progressive, with a small potential (estimated to be 3%) to develop into invasive squamous cell carcinoma. The relative effectiveness of the available treatments is not known for Bowen's disease, and this review attempts to address which is the most effective intervention, with the least side-effects, for cutaneous Bowen's disease. OBJECTIVES: To assess the effects of therapeutic interventions for cutaneous Bowen's disease. SEARCH METHODS: We searched the following databases up to September 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, Issue 9), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), and LILACS (from 1982). We also searched online trials registers. We checked the bibliographies of included and excluded studies and reviews, for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: We included all randomised controlled trials assessing interventions used in Bowen's disease, preferably histologically proven. DATA COLLECTION AND ANALYSIS: Two authors independently carried out study selection and assessment of methodological quality. MAIN RESULTS: The primary outcome measures were complete clearance of lesions after the first treatment cycle and recurrence rate at 12 months. Our secondary outcomes included the number of lesions that cleared after each treatment cycle, the number of treatment cycles needed to achieve clearance, the recurrence rates at > 12 months, cosmetic outcome, quality of life assessment, and adverse outcomes as reported by both participant and clinician.We included 9 studies, with a total of 363 participants. One study demonstrated statistically significantly greater clearance of lesions of Bowen's disease with MAL-PDT (methyl aminolevulinate with photodynamic therapy) when compared with placebo-PDT (RR (risk ratio) 1.68, 95% CI (confidence interval) 1.12 to 2.52; n = 148) or cryotherapy (RR 1.17, 95% CI 1.01 to 1.37; n = 215), but there was no significant difference when MAL-PDT was compared to 5-FU (5-fluorouracil). One study demonstrated statistically significantly greater clearance of lesions with ALA-PDT (5-aminolevulinic acid with photodynamic therapy) versus 5-FU (RR 1.83, 95% CI 1.10 to 3.06; n = 66), but no statistically significant difference in recurrence rates at 12 months (RR 0.33, 95% CI 0.07 to 1.53).Cryotherapy showed no statistically significant difference in clearance rates (RR 0.99, 95% CI 0.78 to 1.26) or recurrences at 1 year (RR 1.48, 95% CI 0.53 to 4.17) when compared to 5-FU in 1 study of 127 participants.One study compared imiquimod to placebo and demonstrated statistically significantly greater clearance rates in the imiquimod group (9/15 lesions) compared to placebo (0/16) (Fisher's Exact P value < 0.001). The imiquimod group did not report any recurrences at 12 months, but at 18 months, 2/16 participants in the placebo group had developed early invasive squamous cell carcinoma. AUTHORS' CONCLUSIONS: Overall, there has been very little good-quality research on treatments for Bowen's disease. There is limited evidence from single studies to suggest MAL-PDT is an effective treatment. Although cosmetic outcomes appear favourable with PDT, five-year follow-up data are needed. Significantly more lesions cleared with MAL-PDT compared to cryotherapy. No significant difference in clearance was seen when MAL-PDT was compared with 5-FU, but one study found a significant difference in clearance in favour of ALA-PDT when compared to 5-FU. There was no significant difference in clearance when cryotherapy was compared to 5-FU.The lack of quality data for surgery and topical cream therapies has limited the scope of this review to one largely about PDT studies. The age group, number, and size of lesions and site(s) affected may all influence therapeutic choice; however, there was not enough evidence available to provide guidance on this. More studies are required in the immunosuppressed populations as different therapeutic options may be preferable. Specific recommendations cannot be made from the data in this review, so we cannot give firm conclusions about the comparative effectiveness of treatments.

Interventions for infantile haemangiomas (strawberry birthmarks) of the skin.

BACKGROUND: Infantile haemangiomas (also known as strawberry birthmarks) are soft, raised swellings of the skin which are usually uncomplicated and tend to regress spontaneously over time. Some haemangiomas occur in high-risk areas or can develop complications; therefore, intervention may be necessary. Various interventions have been proposed, but it is unclear whether any of these interventions are effective. OBJECTIVES: To assess the effects of interventions for infantile haemangiomas. SEARCH STRATEGY: We searched the following databases up to March 2011: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (Clinical Trials) in The Cochrane Library, MEDLINE, EMBASE, PsycINFO, AMED (Allied and Complementary Medicine), LILACS (Latin American and Caribbean Health Science Information database), CINAHL, and reference lists of articles. We also searched online trials registries for ongoing trials and grey literature. SELECTION CRITERIA: We included children with haemangiomas. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles, abstracts, and the full text of publications; extracted data; and assessed risk of bias. MAIN RESULTS: We included 4 studies with a total of 271 participants.One randomised controlled trial (RCT) compared pulsed dye laser (PDL) therapy versus the 'wait and see' approach. At one year PDL was significantly more likely to result in complete clearance. The risk ratio (RR) was 6.10 (95% CI [confidence interval] 1.89 to 19.64); however, there was no difference when clearance was defined as 'complete or minimal residual signs'. Redness was significantly less pronounced in the PDL group, but no differences were seen for height or surface area. Significant increases in atrophy and skin hypopigmentation were seen in the PDL group.One very old RCT assessed radiation versus mock-radiation; there was no significant difference in clearance at six years (RR 1.08, 95% CI 0.63 to 1.87) between the groups, irrespective of the size of the haemangioma and the skin colour.In one small RCT there was a significantly greater reduction in size of the haemangioma with oral prednisolone compared to intravenous methylprednisolone at three months (mean difference [MD] was 58 mm [95% CI 29.24 to 86.76]), and one year. Similar adverse events occurred in both groups.In another small RCT there was a significant reduction in the surface area of the haemangioma with bleomycin compared to the control (RR 21, 95% CI 1.34 to 328.86). AUTHORS' CONCLUSIONS: This review has found limited evidence from individual RCTs to support some of the existing interventions (corticosteroid and PDL) for infantile haemangiomas. There is a need for further high-quality RCTs to validate the findings from these studies, and RCTs to assess the effect of other treatments, in particular relating to propranolol.

Interventions for non-metastatic squamous cell carcinoma of the skin.

BACKGROUND: Squamous cell carcinoma (SCC) is the second most common skin cancer, and is becoming increasingly common around the world. Left untreated, it may spread to other parts of the body, and, although the risk is low, it may ultimately lead to death. Surgical excision is the first line of treatment for most skin SCCs, although other forms of treatment are also used depending upon the nature and site of the tumour and individual participant factors. A multi-professional approach is therefore required for the management of people with this condition. OBJECTIVES: To assess the effects of treatments for primary non-metastatic squamous cell carcinoma of the skin. SEARCH STRATEGY: In February 2010 we searched for relevant trials in The Cochrane Skin Group Specialised Register, The Cochrane Library (Issue 1, 2010), MEDLINE, EMBASE, PsycINFO, AMED, LILACS, and the ongoing trials registries. SELECTION CRITERIA: We only included randomised controlled trials (RCTs) of interventions for primary SCC of the skin. Inclusion criteria were: adults with one or more histologically proven primary SCCs of the skin which had not metastasised. The primary outcome measures were time to recurrence one to five years after treatment, and quality of life. Secondary outcomes included early treatment failure within six months, number of adverse events by the end of treatment, aesthetic appearance as assessed by the participant and clinician, discomfort to the participant during and after treatment, and death. DATA COLLECTION AND ANALYSIS: Two authors (LL, FB-H) independently carried out study selection and assessment of methodological quality and data extraction. MAIN RESULTS: One trial involving 65 people was included. This compared the time to recurrence in participants with aggressive skin SCC who were randomised to receive either adjuvant 13-cis-retinoic acid and interferon alpha after surgery with or without radiation treatment, or no adjuvant therapy after their initial treatment. There was no significant difference in time to recurrence of tumour between the two groups (hazard ratio 1.08, 95% confidence intervals 0.43 to 2.72).Most studies identified from the searches were excluded as they were either uncontrolled case series, did not include participants with invasive primary SCC, or included only participants with recurrent or metastatic disease. AUTHORS' CONCLUSIONS: Little evidence from RCTs comparing the efficacy of different interventions for primary cutaneous SCCs exists. There is a clear need for well-designed randomised studies in order to improve the evidence base for the management of this condition.

The SINS trial: a randomised controlled trial of excisional surgery versus imiquimod 5% cream for nodular and superficial basal cell carcinoma.

BACKGROUND: Basal cell carcinoma is the commonest human cancer. Despite increasing incidence it remains poorly researched. While not life threatening it can cause significant cosmetic disfigurement. Imiquimod, a cream which enhances the body's immune response, may help deal with the number of cases that occur in low-risk sites, especially when good cosmetic results and home use without surgery are needed.This study aims 1. To compare excisional surgery with imiquimod cream for nodular or superficial basal cell carcinoma in low risk sites, with respect to 3 year clinical clearance, cost-effectiveness and cosmetic results. 2. To ascertain if certain phenotypic features and gene polymorphisms predict tumour responsiveness to treatment. METHODS/DESIGN: Five hundred participants with low risk nodular or superficial basal cell carcinoma will be recruited from hospitals to this multi-centre, randomised, parallel group, controlled phase III trial. Treatment in the imiquimod group is for 6 weeks for superficial basal cell carcinoma and 12 weeks for nodular basal cell carcinoma. Both treatment groups are followed up in clinic for 3 years. Primary outcome variable: the proportion of participants with clinical evidence of success (no recurrence) at 3 years. The primary outcome will be compared between the two treatment groups. Secondary outcomes include: i) clinical success at 1, 2 and 5 years, ii) time to first recurrence, iii) cosmetic appearance of lesion site after treatment, iv) level of pain, and v) cost-effectiveness. Safety and tolerability data will also be reported. DISCUSSION: This study protocol describes a pragmatic randomised controlled trial which it is hoped will address the above uncertainties. Three-year results will be available towards the end of 2010. TRIAL REGISTRATION: Meta-register: NCT00066872, Eudract No. 2004-004506-24, ISRCTN48755084.