Surgical excision versus topical 5% 5-fluorouracil and photodynamic therapy in treatment of Bowen's disease: A multicenter randomized controlled trial.

BACKGROUND: Randomized controlled trials comparing the effectiveness of 5-fluorouracil cream, methylaminolevulinate photodynamic therapy (MAL-PDT) and surgical excision in patients with Bowen's disease are lacking. METHODS: In this multicenter noninferiority trial, patients with a histologically proven Bowen's disease of 4-40 mm were randomly assigned to excision with 5 mm margin, 5% 5-fluorouracil cream twice daily for 4 weeks, or 2 sessions of MAL-PDT with 1 week interval. The primary outcome was the proportion of patients with sustained clearance at 12 months after treatment. A noninferiority margin of 22% was used. RESULTS: Between May 2019 and January 2021, 250 patients were randomized. The proportion of patients with sustained clearance was 97.4% (75/77) after excision, 85.7% (66/77) after 5-fluorouracil, and 82.1% (64/78) after MAL-PDT. Absolute differences were -11.7% (95% CI -18.9 to -4.5; P = .0049) for 5-fluorouracil versus excision and -15.4% (95% CI -23.1 to -7.6; P = .00078) for MAL-PDT versus excision. Both noninvasive treatments significantly more often led to good or excellent cosmetic outcome. CONCLUSIONS: Based on our predefined noninferiority margin of 22%, 5-fluorourcail is noninferior to excision and associated with better cosmetic outcome. For MAL-PDT noninferiority to excision cannot be concluded. Therefore, 5-fluorouracil should be preferred over excision and MAL-PDT in treatment of Bowen's disease.

Optical coherence tomography versus punch biopsy for diagnosis of basal cell carcinoma: a multicentre, randomised, non-inferiority trial.

BACKGROUND: Punch biopsy is the gold standard for diagnosis and subtyping of basal cell carcinoma. The aim of this study was to assess whether use of optical coherence tomography (OCT), a non-invasive imaging tool, might avoid the need for biopsy. METHODS: In a multicentre, randomised, non-inferiority trial, patients (aged ≥18 years) with an indication for biopsy of a suspected basal cell carcinoma outside the H-zone (high-risk zone) of the face were randomly assigned (1:1) to receive either OCT or punch biopsy (regular care) via a web-based randomisation system. Patients were enrolled from three participating centres in the Netherlands: Maastricht University Medical Centre+, Catharina Hospital Eindhoven, and Zuyderland Medical Centre Heerlen. Stratification factors for randomisation were participating centre and the grade of clinical basal cell carcinoma suspicion (high vs low). The primary endpoint was the proportion of patients free from a recurrent or residual lesion (malignant or premalignant) 12 months after treatment. Modified intention-to-treat and per-protocol analyses were conducted, with a predefined non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov number, NCT03848078, and is complete. FINDINGS: Between Feb 25, 2019, and Sept 2, 2020, 598 patients were enrolled and randomly assigned to either the regular care group (n=299) or the OCT group (n=299). Data on the primary endpoint were available in 553 patients (n=268 in the regular care group, n=285 in the OCT group). After median follow-up of 12·7 months (IQR 11·2-14·1) in the OCT group and 12·6 months (10·8-14·3) in the regular care group, 253 (94%) of 268 patients in the OCT group and 266 (93%) of 285 patients in the regular care group were free from recurrent or residual lesions (malignant or pre-malignant) 12 months after treatment. According to our modified intention-to-treat analysis, the absolute difference (OCT vs regular care) was 1·07% (95% CI -2·93 to 5·06; one-sided p=0·30), with the lower limit of the 95% CI not exceeding the predefined non-inferiority margin of -10%. Per-protocol analyses led to proportions free from a residual or recurrent lesion (premalignant or malignant) of 95% (250 of 263) in the OCT group and 94% (262 of 278) in the regular care group, and an absolute difference of 0·81% (95% CI -2·98 to 4·60; one-sided p=0·34). INTERPRETATION: OCT-guided diagnosis and treatment of basal cell carcinoma is non-inferior to regular care punch biopsy. Implementation of OCT for diagnosis of basal cell carcinoma could reduce the number of consultations and invasive procedures. FUNDING: The Netherlands Organization for Health Research and Development and Maurits en Anna de Kock Stichting.

Randomized Trial of Four Treatment Approaches for Actinic Keratosis.

BACKGROUND: Actinic keratosis is the most frequent premalignant skin disease in the white population. In current guidelines, no clear recommendations are made about which treatment is preferred. METHODS: We investigated the effectiveness of four frequently used field-directed treatments (for multiple lesions in a continuous area). Patients with a clinical diagnosis of five or more actinic keratosis lesions on the head, involving one continuous area of 25 to 100 cm2, were enrolled at four Dutch hospitals. Patients were randomly assigned to treatment with 5% fluorouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), or 0.015% ingenol mebutate gel. The primary outcome was the proportion of patients with a reduction of 75% or more in the number of actinic keratosis lesions from baseline to 12 months after the end of treatment. Both a modified intention-to-treat analysis and a per-protocol analysis were performed. RESULTS: A total of 624 patients were included from November 2014 through March 2017. At 12 months after the end of treatment, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confidence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3). As compared with fluorouracil, the hazard ratio for treatment failure was 2.03 (95% CI, 1.36 to 3.04) with imiquimod, 2.73 (95% CI, 1.87 to 3.99) with MAL-PDT, and 3.33 (95% CI, 2.29 to 4.85) with ingenol mebutate (P≤0.001 for all comparisons). No unexpected toxic effects were documented. CONCLUSIONS: At 12 months after the end of treatment in patients with multiple actinic keratosis lesions on the head, 5% fluorouracil cream was the most effective of four field-directed treatments. (Funded by the Netherlands Organization for Health Research and Development; ClinicalTrials.gov number, NCT02281682.).

Long-Term Efficacy of Photodynamic Therapy with Fractionated 5-Aminolevulinic Acid 20% versus Conventional Two-Stage Topical Methyl Aminolevulinate for Superficial Basal-Cell Carcinoma.

BACKGROUND: Photodynamic therapy (PDT) is a noninvasive treatment for patients with superficial basal-cell carcinoma (sBCC). The efficacy of PDT may vary with different photosensitizers and treatment schedules. OBJECTIVE: Our objective was to evaluate whether fractionated 5-aminolevulinic acid 20% (ALA)-PDT is superior to conventional two-stage methyl aminolevulinate (MAL)-PDT for sBCC. METHODS: We present the 5 years results of a single-blind, randomized, multicenter trial. 162 patients with a histologically confirmed primary sBCC were randomized to fractionated ALA-PDT or MAL-PDT. RESULTS: The 5-year tumor-free survival rate was 70.7% (95% CI 58.2-80.1%) for ALA-PDT and 76.5% (95% CI 64.4-85.0%) for MAL-PDT. In the first 3 years, there was no significant difference in risk of treatment failure (HR = 1.53, p = 0.283), but in the long-term, the risk of recurrence was significantly lower following MAL-PDT compared to ALA-PDT (HR = 0.125, p = 0.049). As judged by patients, the esthetic result was good-excellent in 96.8% (61/63) and 94.4% (56/59) of patients treated with ALA-PDT and MAL-PDT, respectively (p = 0.631). CONCLUSION: The long-term efficacy is significantly higher for conventional two-stage MAL-PDT than for fractionated ALA-PDT, whereas there was no significant difference in esthetic outcome between the treatments at 5 years after treatment. These results indicate that fractionated ALA-PDT offers no benefit over conventional two-stage MAL-PDT.

Laser-mediated Photodynamic Therapy: An Alternative Treatment for Actinic Keratosis?

Photodynamic therapy (PDT) with light emitting diode (LED) illumination is a frequently used treatment modality for actinic keratosis (AK) with excellent cosmetic outcome. A major disadvantage, however, is the high pain score. Pulsed dye laser (PDL) illumination has been suggested, but the long-term efficacy of this treatment is unknown. In this split-face study we prospectively treated 61 patients with AK, with both LED-PDT and PDL-PDT. The mean change in the number of lesions between the end of follow-up and start of therapy was -4.25 (95% confidence interval (95% CI) -5.07; -3.43) for LED-PDT and -3.88 (95% CI -4,76; -2.99) for PDL-PDT, with a non-significant difference (p = 0.258) of -0.46 (95% CI -1.28; 0.35). The percentage decrease from baseline in the total number of AK was 55.8% and 47.8%, respectively, at 12-month follow-up. Visual analogue scale pain score was lower after PDL (mean 2.64) compared with LED illumination (mean 6.47). These findings indicate that PDL-PDT is an effective alternative illumination source fo.

Superficial hemangioma: pulsed dye laser versus wait-and-see.

BACKGROUND AND OBJECTIVES: Childhood hemangioma is the most common soft tissue tumor of infancy, occurring in 10% of children younger than 1 year old. Ten percent of these infantile hemangiomas involute yearly without intervention. Treatment with the pulsed dye laser (PDL) is the criterion standard for treating vascular lesions. It is well established as the most effective, safest treatment for port-wine stains. Previous studies of the use of PDL treatment in superficial hemangioma showed inconsistent results. Main objectives were to compare the efficacy and adverse effects of PDL treatment with those of observation in the treatment of superficial hemangiomas. Parental quality of life was also assessed. MATERIALS AND METHODS: This was a prospective, randomized, controlled trial in which we enrolled 22 infants aged 1.5 to 5 months old with early hemangiomas with a maximum diameter of 5 cm. We assigned the infants to PDL treatment (n = 11) or observation (n = 11), and followed up until the age of 1 year. Patients in the intervention group were treated using a 595-nm PDL (VBEAM, Candela Corp., Wayland, MA) with a 7-mm spot diameter, 30/10 to 40/10-ms epidermal cooling, a 7- to 15-J/cm(2) fluence range, and a pulse duration of 0.45 to 40.0 ms. During follow-up, color measurements were made (Colori meter; Minolta, Tokyo, Japan), and surface area and echo depth of the hemangioma were determined. RESULTS: No significant differences were seen between the groups at time of inclusion or at the age of 1 year in echo depth (p = .66) or surface area (p = .62). Results were significant for color difference (p = .03) between PDL treatment and observation. Cosmetic outcome judged by an independent panel consisting of a dermatologist, physician assistant, dermatology resident, dermatology nurse, and plastic surgery resident was significantly better in the PDL treatment group (46%) than in the observation group (18%) (p = .006). CONCLUSIONS: Pulsed dye laser is only to be considered as an alternative treatment up to the age of 6 months, at which time parents and physicians consider cosmetic outcome to be a relevant factor, but laser therapy plays a major role in the treatment of residual lesions at older ages.

Risk of Invasive Cutaneous Squamous Cell Carcinoma After Different Treatments for Actinic Keratosis: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Treatment of actinic keratosis (AK) aims to prevent cutaneous squamous cell carcinoma (cSCC). However, whether AK can progress into invasive cSCC is a matter of debate, and little is known about the effect of treatment on preventing cSCC. Objectives: To evaluate the risk of invasive cSCC and factors that may contribute to increased risk in patients with multiple AKs. Design, Setting, and Participants: In this secondary analysis of a multicenter randomized clinical trial, 624 patients with a minimum of 5 AKs within an area of 25 to 100 cm2 on the head were recruited from the Department of Dermatology of 4 hospitals in the Netherlands. Long-term follow-up was performed from July 1, 2019, to December 31, 2020. Interventions: Patients were randomized to treatment with 5% fluorouracil, 5% imiquimod cream, methylaminolevulinate photodynamic therapy, or 0.015% ingenol mebutate gel. Main Outcomes and Measures: The primary outcome was the proportion of patients with invasive cSCC in the target area during follow-up. Secondary outcomes were the associations between risk of invasive cSCC and a priori defined potential prognostic factors, including type of treatment, severity of AK (Olsen grade), history of nonmelanoma skin cancer, and additional treatment. Results: Of the 624 patients (558 [89.4%] male; median age, 73 years [range, 48-94 years]) in the study, 26 were diagnosed with a histologically proven invasive cSCC in the target area during follow-up. The total 4-year risk of developing cSCC in a previously treated area of AK was 3.7% (95% CI, 2.4%-5.7%), varying from 2.2% (95% CI, 0.7%-6.6%) in patients treated with fluorouracil to 5.8% (95% CI, 2.9%-11.3%) in patients treated with imiquimod. In patients with severe AK (Olsen grade III), the risk was 20.9% (95% CI, 10.8%-38.1%), and the risk was especially high (33.5%; 95% CI, 18.2%-56.3%) in patients with severe AK who needed additional treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, risk of invasive cSCC was highest in patients with Olsen grade III AK and was substantially increased in patients who received additional treatment. These patients should be closely followed up after treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02281682.