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.

Effectiveness of a patient decision aid for patients with superficial basal cell carcinoma: A pre- and post-implementation study.

OBJECTIVE: This study evaluates whether using a patient decision aid (PDA) for patients with superficial basal-cell carcinoma (sBCC) results in a decreased decisional conflict level and increased knowledge. METHODS: In a prospective multicentre study, patient groups were included before and after implementation of a PDA. Decisional conflict levels were compared directly after making the treatment decision, measured once as the mean score on the decisional conflict scale (DCS). Higher scores correspond with higher conflict levels (0-100). Secondary outcomes were knowledge on treatment options, recognizing a BCC, and risk factors for developing a BCC measured on an adapted version of a validated knowledge questionnaire for melanoma patients, and patient satisfaction with the PDA. RESULTS: Data was available for 103 patients in the control-group and 109 in the PDA-group. The mean DCS score in the control-group was 22.78 (SD 14.76) compared to 22.34 (SD 14.54) in the PDA-group; the decrease was non-significant (p = 0.828). The average percentage correct answers on the knowledge questionnaire increased from 76.5% in the control-group to 80.5% in the PDA-group (p = 0.044). According to the majority of patients in the PDA-group (73.7%) the PDA had added value. CONCLUSION: Using the PDA had no significant effect on decisional conflict levels, but increased overall knowledge on relevant issues concerning sBCC. PRACTICE IMPLICATIONS: The PDA can be used as an informational tool by patients with sBCC.

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.

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.

[Overtreatment of patients with basal cell carcinoma: active surveillance should be considered more often]. / Overbehandeling van patiënten met basaalcelcarcinoom.

Basal cell carcinoma (BCC) is the most common cancer type in the Netherlands and frequently diagnosed in older adults. Unlike other common forms of skin cancer (squamous cell carcinoma and melanoma), BCC generally grows slowly and the risk of metastasis and/or death is extremely small. In the first years after presentation, BCC often causes no or only minor complaints. Nevertheless, the vast majority of patients with BCC are treated immediately after diagnosis, usually with surgical excision. We think that overtreatment of patients with BCC is common and active surveillance may be an excellent alternative for patients with a limited life expectancy and should therefore be considered more often.

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.

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.

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.

Treatment of Actinic Keratosis: Does Effectiveness Depend on the Location?

This is a comment on a network meta-analysis that evaluated the ranking of treatments for actinic keratosis outside the head and neck. The results of a limited number of heterogeneous studies contrast with the results of studies in the head and neck area. The extent to which these results can be generalized to larger treatment fields or areas with extensive field cancerization is uncertain.

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.

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.

Optical Coherence Tomography for Noninvasive Diagnosis and Subtyping of Basal Cell Carcinoma: A Prospective Cohort Study.

Noninvasive diagnostic strategies such as optical coherence tomography (OCT) enable detailed examination of skin tissue architecture and have potential for identification and subtyping of basal cell carcinoma (BCC). To evaluate the additional diagnostic value of OCT, a prospective cohort study was performed in 182 patients with 250 lesions suspected for non-melanoma skin premalignancies requiring a biopsy. Accuracy of BCC diagnosis and subtype on the basis of clinical examination (CE) of patients was compared with that on the basis of OCT scans in conjunction with clinical images of lesions (cOCT). Confidence levels were recorded on a 5-point scale, where score 0 indicated absence of BCC and scores 1-4 indicated increasing suspicion of BCC. Diagnostic performance parameters were compared using histopathologic diagnosis as gold standard. The patient-based area under the receiver operating characteristic curve (AUC) increased from 85.6% for CE to 91.2% for cOCT (P = 0.061) and the lesion-based AUC from 82.7% to 91.3% (P < 0.001). When confidence scores 1-4 were defined as positive, patient-based specificity increased from 47.5% (CE alone) to 76.8% (cOCT) at similar sensitivity (97.6% and 95.2%, respectively). cOCT slightly improved the ability to discriminate between superficial and nonsuperficial BCC subtypes and seemed to be a valuable addition to CE alone in the diagnosis and subtyping of BCC.

European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 2. Treatment.

In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed. Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent cSCC type), first-line treatment is surgical excision with postoperative margin assessment or microscopically controlled sugery. Safety margins containing clinical normal-appearing tissue around the tumour during surgical excision and negative margins as reported in the pathology report are necessary to minimise the risk of local recurrence and metastasis. In case of positive margins, a re-excision shall be done, for operable cases. Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. Multidisciplinary board decisions are mandatory for all patients with advanced disease who require more than surgery. Patients should be engaged with informed decisions on management and be provided with best supportive care to optimise symptom management and improve quality of life. Frequency of follow-up visits and investigations for subsequent new cSCC depend on underlying risk characteristics.

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.