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.

Prognostic factors for treatment failure of photodynamic therapy and 5-fluorouracil in Bowen's disease.

Introduction Little is known about prognostic factors that may influence the response to non-invasive treatments of patients with Bowen's disease. The aim of this study was to identify patient and lesion characteristics that are associated with higher risk of treatment failure after 5-fluorouracil and PDT in Bowen's disease. The hypothesis that thickness of the Bowen's lesion and extension along the hair follicle are associated with risk of treatment failure after noninvasive treatment was also explored. Methods Data were derived from a non-inferiority randomized trial in which 169 patients were treated with 5% 5-fluorouracil cream twice daily for 4 weeks or 2 sessions of MAL-PDT with 1 week interval. All patients had histologically confirmed Bowen's disease of 4-40mm. The initial 3 mm biopsy specimens were re-examined to measure the maximum histological lesion thickness and extension along the hair follicle. To evaluate the association between potential risk factors for treatment failure at one year follow-up, univariate and multivariate logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals and p-values. Results Histological lesion thickness was not significantly associated with treatment failure (OR 0.84, p=0.806), nor was involvement of the hair follicle (OR 1.12 , p=0.813). Lesion diameter was the only risk factor that was significantly associated with one-year risk of treatment failure (OR=1.08 per mm increase, p=0.021).When using the median value of 10 mm as cut-off point, the risk of treatment failure was 23.4% for lesions > 10 mm compared to 10.3% for lesions ≤10 mm (OR 2.66, p=0.028). Conclusions Only clinical lesion diameter was identified as a prognostic factor for response to non-invasive therapy in 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.

Rate and Characteristics of Incompletely Excised Cutaneous Squamous Cell Carcinoma: A Dermatological Daily Practice Multicenter Prospective Cohort Study.

BACKGROUND: Incomplete excision of squamous cell carcinoma (cSCC) is associated with an increased risk of recurrence, metastasis, and mortality. OBJECTIVE: To determine the rate and characteristics of incompletely excised cSCC in a dermatological daily practice setting. METHODS: Prospective study of all patients who gave informed consent, with a cSCC treated with standard excision (SE) at 1 of 6 Departments of Dermatology in the Netherlands between 2015 and 2017. Pathological reports were screened to detect all incompletely excised cSCCs. RESULTS: A total of 592 patients with 679 cSCCs were included, whereby most cases were low risk cSCC (89%). The rate of incompletely excised cSCC was 4% ( n = 26), and the majority were high-risk cSCCs of which 24 invaded the deep excision margin. CONCLUSION: This prospective study showed that in a dermatological setting, the risk of an incompletely excised cSCC is low (4%) for a cohort that was dominated by low-risk cSCCs. Most incompletely excised cSCCs were of high risk, and incompleteness was almost always at the deep margins. These results suggest that for high-risk cSCC, one should pay attention especially to the deep margin when performing SE, and/or microscopic surgery should be considered.

Diagnostic Value of Optical Coherence Tomography Image Features for Diagnosis of Basal Cell Carcinoma.

Optical coherence tomography (OCT) is a non-invasive diagnostic method. Numerous morphological OCT features have been described for diagnosis of basal cell carcinoma (BCC). The aim of this study is to evaluate the diagnostic value of established OCT features and to explore whether the use of a small set of OCT features enables accurate discrimination between BCC and non-BCC lesions and between BCC subtypes. For each lesion, the presence or absence of specific OCT features was recorded. Histopathology was used as a gold standard. Diagnostic parameters were calculated for each OCT feature, and multivariate logistic regression analyses were performed to evaluate the loss in discriminative ability when using a small subset of OCT features instead of all features that are characteristic for BCC according to the literature. The results show that the use of a limited number of OCT features allows for good discrimination of superficial BCC from non-superficial BCC and non-BCC lesions. The prevalence of BCC was 75.3% (225/299) and the proposed diagnostic algorithm enabled detection of 97.8% of BCC lesions (220/225). Subtyping without the need for biopsy was possible in 132 of 299 patients (44%), with a predictive value for presence of superficial BCC of 84.3% vs 98.8% for presence of non-superficial BCC.

Topical Application of Glycerol Increases Penetration Depth of Optical Coherence Tomography in Diagnosis of Basal Cell Carcinoma.

Optical coherence tomography is a non-invasive imaging technique that enables high-resolution in vivo imaging of skin. Although optical coherence tomography is promising for diagnosing basal cell carcinoma, its limited penetration depth may impede basal cell carcinoma subtyping. This study evaluated whether topical application of glycerol can increase penetration depth and improve the image quality and visibility of characteristic features of basal cell carcinoma. A total of 61 patients with a total of 72 basal cell carcinomas were included. Optical coherence tomography scans were obtained before and after application of an 85% glyce-rol solution. The mean penetration depth of each optical coherence tomography scan was acquired by automatically tracing both skin surface and the point of signal loss using a custom-made MATLAB program. Mean ± standard deviation penetration depth increased from 883 ± 108 to 904 ± 88 µm before and after glycerol application, respectively (p = 0.005). Topical application of glycerol leads to a significant 2.4% increase in penetration depth. However, no significant differences in image quality and visibility of basal cell carcinoma features were found.

Surgery versus combined treatment with curettage and imiquimod for nodular basal cell carcinoma: One-year results of a noninferiority, randomized, controlled trial.

PURPOSE: Nodular basal cell carcinoma (nBCC) is mostly treated with surgical excision. Interest in minimally invasive treatment of these low-risk tumors is increasing. We assessed the effectiveness of nBCC treatment with curettage and imiquimod cream compared with surgical excision. METHODS: Patients with nBCC included in this randomized, controlled noninferiority trial were randomly assigned to either a curettage and imiquimod cream group or a surgical excision group. The primary endpoint was the proportion of patients free from treatment failure 1 year after the end of treatment. A prespecified noninferiority margin of 8% was used. A modified intention-to-treat and a per-protocol analysis was performed (ClinicalTrials.gov identifier NCT02242929). RESULTS: One hundred forty-five patients were randomized: 73 to the curettage and imiquimod cream group and 72 to the surgical excision group. The proportion of patients free of recurrence after 12 months was 86.3% (63/73) for the curettage and imiquimod group and 100% (72/72) for the surgical excision group. The difference in efficacy was -13.7% (95% confidence interval -21.6% to -5.8%; 1-sided P = .0004) favoring surgical excision. CONCLUSION: Noninferiority of curettage and imiquimod cream cannot be concluded. Given the still high efficacy of curettage and imiquimod cream and the indolent growth pattern of nBCC, curettage and imiquimod could still be a valuable treatment option with the possibility to prevent overuse of excisions. However, it cannot replace surgical excision.

Single versus Multiple Level Sectioning for the Subtyping of Basal-Cell Carcinoma: A Retrospective Study.

BACKGROUND: The histological subtype of basal-cell carcinoma (BCC) is often based on a punch biopsy; only a small part is evaluated, possibly leading to misclassification. Consensus on the optimal approach to process punch biopsies is lacking, though accurate subtyping is important for appropriate treatment. OBJECTIVE: The aim is to investigate whether evaluating 4 levels of a punch biopsy instead of 1 or 2 levels leads to more accurate subtyping of BCC. METHODS: In a retrospective study we evaluated 87 punch biopsies of histologically confirmed BCCs. The primary outcome was the proportion of "more aggressive" BCCs (nonsuperficial vs. superficial, infiltrative vs. nodular subtype) that was missed by evaluation on 1 or 2 levels, using 4-level diagnosis as reference standard. RESULTS: Eighty-five cases were available for analysis. Subtyping based on 1 level resulted in discrepancies with 4-level diagnosis in 16.5% of all cases. Underdiagnosis occurred in 14 of 58 nonsuperficial BCCs (24.1%, 95% CI: 13.9-37.2). Seven of 38 nodular BCCs (18.4%, 95% CI: 7.74-34.3) were diagnosed as superficial in 1 level, and 7 of 20 infiltrative BCCs (35%, 95% CI: 15.4-59.2) were diagnosed as superficial (n = 2) or nodular (n = 5) in 1 level. CONCLUSION: In order to maximize correct subtyping and plan appropriate treatment, we advise to evaluate at least 2, but preferably more, levels of a punch biopsy to determine the BCC subtype.

Cumulative Sum Analysis for the Learning Curve of Optical Coherence Tomography Assisted Diagnosis of Basal Cell Carcinoma.

The amount of training needed to correctly interpret optical coherence tomography scans of the skin is undefined. The aim of this study was to illustrate how cumulative sum charts can be used to determine how many optical coherence tomography scans novice assessors should evaluate in order to obtain competence in diagnosing basal cell carcinoma. Four hundred lesions suspected for non-melanoma skin cancer were evaluated by optical coherence tomography in combination with clinical photographs, using a 5-point confidence scale. The diagnostic error rate (sum of false-negative and false-positive optical coherence tomography results/total number of cases) was used to evaluate performance, with histopathological diagnosis as the reference standard. Acceptable and unacceptable error rates were set at 16% and 25%, respectively. Adequate performance was reached after assessing 183-311 scans, dependent on the cut-off for a positive test result. In conclusion, cumulative sum analysis is useful to monitor the progress of optical coherence tomography trainees. The caseload necessary for training is substantial.

Histologic subtype of treatment failures after noninvasive therapy for superficial basal cell carcinoma: An observational study.

BACKGROUND: There have been concerns that recurrences after noninvasive therapy for basal cell carcinoma (BCC) transform into a "more aggressive" histologic subtype. OBJECTIVE: We sought to evaluate the proportion of patients with a nonsuperficial treatment failure after noninvasive therapy for superficial BCC. METHODS: An observational study was performed using data from a single blind, noninferiority, randomized controlled trial (March 2008-August 2010) with 5-year follow-up in patients with primary superficial BCC treated with methylaminolevulinate-photodynamic therapy, 5-fluorouracil, or imiquimod. Data were used from 166 adults with a histologically confirmed treatment failure. RESULTS: A nonsuperficial subtype was found in 64 of 166 treatment failures (38.6%). Proportions with a more aggressive subtype than the primary tumor were 51.3% (38/74) for early and 28.3% (26/92) for later treatment failures (P = .003). The proportion of more aggressive early failures was significantly lower after imiquimod (26.3%) compared with methylaminolevulinate-photodynamic therapy (54.8%, P = .086) and 5-fluorouracil (66.7%, P = .011). LIMITATIONS: There was limited information on the exact time of occurrence of treatment failures. CONCLUSION: More aggressive treatment failure recurrences after noninvasive therapy for superficial BCC occur most often within the first 3 months posttreatment, probably indicating underdiagnosis of more aggressive components in the primary tumor rather than transformation.

Risk Factors for Surgical Site Infections in Dermatological Surgery.

Current literature on risk factors for surgical site infection (SSI) in dermatological surgery in the absence of antibiotic prophylaxis is limited. The aim of this study was to retrospectively evaluate patients presenting for dermatological surgery. A total of 1,977 procedures were reviewed. SSI was clinically suspected in 79 (4.0%) patients and confirmed by culture in 38 (1.9%). Using the strictest definition of SSI (clinical symptoms with positive culture) significantly higher risk of SSI was found for location on the ear (odds ratio (OR) 6.03, 95% confidence interval (95% CI) 2.12-17.15), larger defects (OR 1.08 per cm2 increase, 95% CI 1.03-1.14), closure with flaps (OR 6.35, 95% CI 1.33-30.28) and secondary intention (OR 3.01, 95% CI 1.11-8.13). These characteristics were also associated with higher risk of clinically suspected SSI regardless of culture results with slightly lower ORs. In conclusion, the risk of acquiring a SSI is increased in surgeries performed on the ear, in larger wounds and in defects closed with flaps or healed by secondary intention.

A Clinical Prediction Model for Surgical Site Infections in Dermatological Surgery.

To adequately identify patients at risk for surgical site infection in dermatological surgery and effectively prescribe antibiotic prophylaxis, a prediction model may be helpful. Such a model was developed using data from 1,407 patients who underwent dermatological surgery without antibiotic prophylaxis. The multivariable logistic regression model included type of closure, tumour location and defect size as risk factors. Bootstrapping was used for internal validation. The overall performance of the model was good, with an area under the curve of 84.1%. The decision curve analysis showed that the model is potentially useful if one is willing to treat more than 8 patients with antibiotic prophylaxis to avoid one infection. For those who prefer more restrictive use of antibiotic prophylaxis, a default strategy of treating no patients at all with prophylaxis would be the best choice. External validation of the model is required before it can be widely applied.

Aesthetic outcome and complications of simple interrupted versus running subcuticular sutures in facial surgery: A randomized controlled trial.

BACKGROUND: The suturing technique and its associated complications could affect cosmetic outcome after facial surgery. Literature on this topic is limited. OBJECTIVE: To compare the cosmetic results 12 months after treatment and complications associated with simple interrupted sutures (SIS) versus running subcuticular sutures (RSS) in facial surgery. METHODS: A randomized, controlled multicenter trial was performed. Adults receiving dermatologic surgery on the face were randomized to receive SIS or RSS for wound closure. The primary outcome was the overall opinion score on the Patient and Observer Scar Assessment Scale (POSAS) 12 months after surgery. Secondary outcomes were the complication rates and scores according to alternative methods for assessment of cosmetic outcome. The observer of cosmetic outcome was blinded to treatment assignment. RESULTS: 142 patients were randomized to receive SIS (n = 73) or RSS (n = 69). Twelve months after surgery, the median score of the overall opinion on the POSAS was 2.0 (range 1-8) according to the patients and 3.0 (range 1-8) according to the observer in both groups. In the RSS group, hyper- or hypoesthesia was reported more often. LIMITATIONS: The cosmetic result was assessed by 1 observer. CONCLUSION: SIS and RSS in facial surgery resulted in comparable cosmetic outcomes. RSS was more often associated with hyper- or hypoesthesia.

The effect of topical diclofenac 3% and calcitriol 3 µg/g on superficial basal cell carcinoma (sBCC) and nodular basal cell carcinoma (nBCC): A phase II, randomized controlled trial.

BACKGROUND: Nonsteroidal anti-inflammatory drugs and vitamin-D derivatives can target signaling pathways activated in basal cell carcinoma (BCC). OBJECTIVE: We investigated the efficacy of topically applied diclofenac sodium 3% gel, calcitriol 3 µg/g ointment, and a combination of both in superficial BCC (sBCC) and nodular BCC. METHODS: Patients with a primary, histologically proven sBCC (n = 64) or nodular BCC (n = 64) were randomized to topical diclofenac, calcitriol, combination of both, or no topical treatment (control group). After self-application twice daily under occlusion (8 weeks), tumors were excised. Primary outcome was posttreatment expression levels of proliferation (Ki-67) and antiapoptosis (B-cell lymphoma [Bcl-2]) immunohistochemical markers. Secondary outcomes were histologic clearance, adverse events, application-site reactions, and patient compliance. RESULTS: sBCC treated with diclofenac showed a significant decrease in Ki-67 (P < .001) and Bcl-2 (P = .001), and after combination therapy for Ki-67 (P = .012). Complete histologic tumor regression was seen in 64.3% (P = .0003) of sBCC (diclofenac) and 43.8% (P = .007) of sBCC (combination therapy) compared with 0.0% of controls. No significant changes were found in nodular BCC. Application-site reactions were mostly mild to moderate. LIMITATIONS: The sample size was small. CONCLUSION: Our results suggest that topical diclofenac is a promising new treatment for sBCC. Its mode of action differs from available noninvasive therapies, and thus has an additive value.