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.

Intralesional photodynamic therapy induces apoptosis in basal cell carcinoma and Bowen's disease through caspase 3 and granzyme B.

BACKGROUND: Photodynamic therapy (PDT) is used to treat cutaneous cancers. It may induce cell death through direct and indirect means, including apoptosis, inflammation and certain immune mechanisms, with the depth of penetration as a potential modifying factor. OBJECTIVES: To examine the pathways of apoptosis in the intralesional PDT of basal cell carcinoma (BCC) and intraepidermal squamous cell carcinoma (Bowen's disease). METHODS: Sixteen patients with superficial or nodular BCC and Bowen's disease were treated with intralesional aminolevulinic acid-PDT. Biopsies were taken at baseline and 24 h post-PDT, and sections were examined by immunohistochemistry for the expression of markers of apoptosis, such as caspase 3, involved in the intrinsic apoptotic pathway, granzyme B, a caspase-independent apoptotic mediator, and the proapoptotic markers BAX and BAK. RESULTS: Apoptotic cells stained with TUNEL showed statistically significant staining at 24 h post PDT (p < 0.01 in both BCC and Bowen's lesions). Caspase 3 (p < 0.01 in BCC and p < 0.05 in Bowen's) and granzyme B (p < 0.01 in BCC and p < 0.01 in Bowen's) were significantly increased at 24 h post-PDT. BAX expression was apparently increased compared to baseline in Bowen's lesions at 24 h post-PDT, whereas Bak was upregulated both in BCC and Bowen's disease at baseline and at 24 h post-PDT. CONCLUSION: Intralesional PDT induces apoptosis in BCC and Bowen's disease via common and alternative apoptotic pathways involving granzyme B. Proapoptotic factors Bak in both BCC and Bowen and Bax in Bowen's disease appear to increase by intralesional PDT at 24 h.

Cryosurgery and 5-Fluorouracil Combination Therapy for Treatment of Bowen's Disease and Superficial Basal Cell Carcinoma.

BACKGROUND: Non-melanoma skin cancer (NMSC), which includes both Bowen's disease (BD) and superficial basal cell carcinoma (sBCC), is the most commonly diagnosed cancer in Canada. BD and sBCC are amenable to minimally invasive treatments however, large-scale studies assessing long-term outcomes are lacking, particularly regarding the timing and duration of non-invasive combination treatments. OBJECTIVE: Examine the clinical cure rate of BD and sBCC using a combination treatment consisting of a single cycle of cryotherapy followed by a three to four-week course of topical 5-fluorouracil (5-FU). METHODS: Retrospective chart review at a single center. Inclusion criteria included histology-proven sBCC or BD treated with either a combination protocol, cryosurgery, or 5-FU alone. RESULTS: 310 biopsy-confirmed cases of BD and 176 biopsy-confirmed cases of sBCC were analyzed. Of these, 229 cases of BD and 61 cases of sBCC were treated with cryosurgery and immediate 5-FU application, yielding a clearance rate of 90% and 86.9% at 6 months from initial treatment. CONCLUSION: Cryosurgery followed by immediate 5-FU use may be an effective mode of treatment for BD and sBCC, negating the need for invasive procedures and allowing for increased accessibility. Further studies with longer follow-up intervals, comparisons with other non-invasive treatments, and evidence of histologic cure are required. J Drugs Dermatol. 2023;22(12):1166-1171. doi:10.36849/JDD.7378.

Immunocryosurgery is a safe and feasible treatment for basal cell carcinoma and Bowen disease in renal transplant recipients.

Keratinocyte skin carcinomas (squamous cell carcinoma, basal cell carcinoma [BCC], Bowen disease [BD]) inflict significant morbidity and constitute a treatment challenge in renal transplant recipients (RTR). Immunocryosurgery has shown efficacy >95% in the treatment of BCC and BD in immunocompetent patients. The present study evaluated the safety, feasibility and efficacy, of immunocryosurgery in the treatment of BCC and BD in a series of RTR. During a 3-year period, biopsy-confirmed cases of BCC and BD were treated with a standard immunocryosurgery cycle (5 weeks daily imiquimod and a session of cryosurgery at day 14). Safety was evaluated by comparing graft function markers between immunocryosurgery treated RTR patients and matched controls. Ten BCC (8 nodular, 1 basosquamous, 1 superficial; diameter 6-14 mm; mean 9.2 mm) and nine BD disease lesions in nine patients (7 men, 2 women; age range: 54-70 years, mean: 62.1 years) were treated with immunocryosurgery and followed-up for two to 5 years. Five BCC were located on the "H area" of the face. No patient showed clinical or laboratory signs of transplant dysfunction during treatment or follow-up. Seven out of 10 BCC lesions cleared completely after one 5-week immunocryosurgery cycle, two cleared after repeat and intensified treatment cycles and one responded only partially (clearance rate: 90%). Seven out of nine BD lesions cleared after one 5-week immunocryosurgery cycle and one lesion after two cycles (clearance rate: 88.9%). In conclusion, immunocryosurgery is a safe, feasible and effective minimally invasive treatment alternative to standard surgical modalities for BCC and BD in RTR.

Efficacy of Photodynamic Therapy for the Treatment of Bowen's Disease: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Photodynamic therapy is an established treatment option for Bowen's disease. Our meta-analysis was aimed at evaluating the efficacy and recurrence of photodynamic therapy or other topical treatments (5-fluorouracil, cryotherapy) and of photodynamic therapy alone or in combination with other therapies (ablative fractional CO2 laser or plum-blossom needle) for the treatment of Bowen's disease. METHODS: Trials that met our inclusion criteria were identified from PubMed, EMBASE, Web of Science, and Cochrane Library databases, and meta-analyses were conducted with RevMan V.5.4. The risk of bias was estimated with the Cochrane Collaboration's risk of bias tools. Complete response rate, recurrence, pain/visual analogue scale score, cosmetic outcome, and adverse events were considered as outcomes. RESULTS: Of the 2,439 records initially retrieved, 8 randomized controlled trials were included in this meta-analysis. According to our analyses, photodynamic therapy exhibited a significantly higher complete response rate (RR = 1.36, 95% CI [1.01, 1.84], I2 = 86%, p = 0.04), less recurrence (RR = 0.53, 95% CI [0.30, 0.95], I2 = 0%, p = 0.03), and better cosmetic outcome (RR = 1.34, 95% CI [1.15, 1.56], I2 = 0%, p = 0.0002) compared with other treatments. Moreover, there was a significant difference between the complete response rate of photodynamic therapy combined with ablative fractional CO2 laser and that of photodynamic therapy (RR = 1.85, 95% CI [1.38, 2.49], I2 = 0%, p < 0.0001). Photodynamic therapy combined with ablative fractional CO2 laser or plum-blossom needle also showed significantly less recurrence (RR = 0.21, 95% CI [0.09, 0.51], I2 = 0%, p = 0.0005) and a lower visual analogue scale score (RR = 0.51, 95% CI [0.06, 0.96], I2 = 0%, p = 0.03) than photodynamic therapy alone. However, there was no significant difference in the complete response rate between photodynamic therapy combined with ablative continuous CO2 laser and photodynamic therapy combined with ablative fractional CO2 laser (RR = 1.00, 95% CI [0.54, 1.86], I2 not applicable, p = 1.00). CONCLUSIONS: This meta-analysis shows that photodynamic therapy can be used in the treatment of Bowen's disease with better efficacy, less recurrence, and better cosmetic outcomes than cryotherapy and 5-FU. Some methods, including ablative fractional CO2 laser, can be applied in combination with photodynamic therapy to improve efficacy. However, which laser-assisted photodynamic therapy scheme has the most advantages in the treatment of Bowen's disease warrants further exploration.

Durable Clearance Rate of Photodynamic Therapy for Bowen Disease and Cutaneous Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Although surgery is the treatment of choice for Bowen disease (BD) and cutaneous squamous cell carcinoma (cSCC), nonsurgical treatments such as photodynamic therapy (PDT) may be preferred for select tumors. Previous meta-analysis have failed to gather strong evidence to recommend PDT. OBJECTIVE: This study evaluates the effectiveness of PDT in the treatment of cSCC and BD for clearance rate (CR) after 1 year. METHODS: A literature search of studies of biopsy-proven BD and cSCC treated with PDT was performed. Pooled CRs were estimated. Subgroup analyses were performed based on follow-up, treatment regimen, lesion size, and site. RESULTS: Forty-three studies were included, enrolling 1943 BD lesions and 282 SCC lesions. Pooled CRs for BD and SCC were 76% (95% CI: 71%-80%; I2 = 78.9%) and 51% (95% CI: 35%-66%; I2 = 85.7%), respectively. CONCLUSION: Our findings support the selective use of PDT for BD; however, patients should be advised of potential for recurrence. Although PDT can be used for certain cases of cSCC, the high rate of treatment failure necessitates close surveillance for residual or recurrent disease. Further studies are needed to justify the usage of PDT in the treatment of BD and cSCC.

[Photodynamic therapy-trends and new developments]. / Photodynamische Therapie ­ Trends und neue Entwicklungen.

Photodynamic therapy (PDT) is a licensed and established procedure for the treatment of actinic keratosis, basal cell carcinoma, and Bowen's disease, but there are several new and clinically relevant developments and trends. These concern on the one hand the main components of PDT, which are the photosensitizer and the light source. Furthermore, modifications and therapy combinations have been developed that lead to an improved therapeutic efficacy. An important aspect of field-directed PDT is also skin cancer prevention. Finally, PDT has been used successfully for nonlicensed indications including inflammatory diseases and skin rejuvenation. This article focuses on these new developments and on recent guideline recommendations.

Efficacy of Imiquimod 3.75% for the treatment of extensive Bowen's disease of the face in an elderly patient.

Bowen's disease is a cutaneous squamous cell carcinoma (SCC) in situ with a potential risk of progression to invasive SCC. Despite the high number of approved treatments, elderly patients with extensive lesions of critical sites may represent a therapeutical challenge, especially in cases of treatment failure or recalcitrant disease. Here, we report the successfully use of topical Imiquimod 3.75% to treat an extensive Bowen's disease of the cheek in an elderly.

[Regression of cutaneous basal cell and squamous cell carcinoma under pembrolizumab]. / Régression de carcinomes basocellulaire et épidermoïde cutanés sous pembrolizumab.

BACKGROUND: The recommended treatments for advanced squamous cell carcinoma (SCC) (chemotherapy, radiotherapy, anti-EGFR) and advanced basal cell carcinoma (BCC) (vismodegib and sonidegib) have many side effects. Nivolumab (anti-PD1 antibody) may be used as second-line therapy in SCC of the head and neck. We report the case of a patient with advanced SCC and BCC which regressed under pembrolizumab. PATIENTS AND METHODS: A 69-year-old man consulted for a large vertex SCC measuring 15cm in diameter. He also had BCC on the left nostril and sternal Bowen disease. Radiological assessment revealed cervical and parotid lymph node involvement. Treatment with pembrolizumab 2mg/kg every 3 weeks was decided at a Multidisciplinary Concertation Meeting. Tumor regression of the vertex SCC was noted at the third course of treatment, as well as regression of the nasal BCC and the sternal Bowen disease. A complete response was observed after 11 courses of treatment for SCC, 7 courses for BCC, and 10 courses for Bowen disease. CONCLUSION: We report an original case of cure of BCC with anti-PD1 (pembrolizumab) prescribed for locally advanced inoperable SCC. The place of this treatment in the therapeutic arsenal remains to be defined. Clinical trials are in progress concerning use of this treatment in advanced cutaneous SCC and inoperable BCC.

Long-term efficacy of photodynamic therapy with methyl aminolevulinate in treating Bowen's disease in clinical practice: A retrospective cohort study (2006-2017).

BACKGROUND: Photodynamic treatment with methyl aminolevulinate (MAL-PDT) is considered an effective and highly recommended treatment for Bowen's disease. However, its long-term efficacy remains to be established, as significant differences have been reported in this respect. OBJECTIVE: The aim of the present study was to describe the results of a retrospective analysis of patients with Bowen's disease treated with MAL-PDT during the period 2006-17 at the Costa del Sol Hospital (Marbella, Spain). MATERIAL AND METHODS: This study is based on a retrospective descriptive analysis of the clinical records of patients treated with MAL-PDT from June 2006 to September 2017. The analysis was based on calculating the mean and standard deviation values for the quantitative variables, and frequency distributions for the qualitative ones. The survival curves were plotted by the Kaplan-Meier method, and the log-rank test was used to assess differences in survival between groups. A cox regression analysis was performed to clarify the significant prognostic factors. RESULTS: A total of 537 tumours with histologically confirmed Bowen's disease were treated with MAL-PDT. Recurrence-free survival at one year was 88%, and at 5 years, 71%. Tumour size >300 mm2 (≥21 mm in diameter P = 0.019), its location in the upper extremities (P = 0.029) and patient's age <70 years (P = 0.028) were all associated with an increased risk of recurrence. LIMITATIONS: Given the retrospective design of our study, the possible existence of information bias cannot be ruled out. CONCLUSIONS: Although it is an appropriate treatment option for patients with Bowen's disease, MAL-PDT presents a risk of recurrence of almost 30% at 5 years. Larger lesions (>300 mm2 ; ≥21 mm in diameter) are more likely to recur than smaller ones. Therefore, appropriate selection is needed of the tumour to be treated, and prolonged follow-up should be provided.

European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 1: treatment delivery and established indications - actinic keratoses, Bowen's disease and basal cell carcinomas.

Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, Bowen's disease (squamous cell carcinoma in situ), superficial and certain thin basal cell carcinomas. Recurrence rates when standard treatment protocols are used are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as lesional and field therapies and has the potential to delay/reduce the development of new lesions. A protocol using daylight to treat actinic keratoses is widely practised, with conventional PDT using a red light after typically a 3-h period of occlusion employed for other superficial skin cancer indications as well as for actinic keratoses when daylight therapy is not feasible. PDT is a well-tolerated therapy although discomfort associated with conventional protocol may require pain-reduction measures. PDT using daylight is associated with no or minimal pain and preferred by patient. There is an emerging literature on enhancing conventional PDT protocols or combined PDT with another treatment to increase response rates. This guideline, published over two parts, considers all current approved and emerging indications for the use of topical PDT in dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence.

Treatment of Arsenic-Induced Bowen's Disease With Topical 5-Fluorouracil

Here, we present a case of arsenic-induced Bowen's disease treated with a regimen consisting of topical 5-fluouracil and oral nicotinamide. The use of this therapy modality resulted in near complete resolution of all of the patient's lesions except for those on her palms, soles, and scalp. Excellent wound care and treatment adherence were major factors contributing to the success of this treatment option. Our results ultimately provide an alternative approach to treating multiple arsenical keratoses in patients who are limited to a drug plan involving 5-FU and oral nicotinamide and who are able to be rigorously compliant with application of medication and wound care. J Drugs Dermatol. 2019;18(5):477-479.

Multiple Bowen's diseases and basal cell carcinomas in a patient with acute promyelocytic leukemia treated with arsenic trioxide: A case report and effective treatment with photodynamic therapy.

It is very rare that multiple Bowen's disease (BD) and basal cell carcinoma (BCC) lesions develop in a single patient. Routine therapy for the multiple lesions is not satisfactory. The present authors report on a patient who had developed multiple BD and BCC lesions for 12 years after arsenic trioxide treatment for his acute promyelocytic leukemia 20 years before. The patient with multiple lesions was successfully treated with photodynamic therapy.

Enhancement of Photodynamic Therapy for Bowen's Disease Using Plum-Blossom Needling to Augment Drug Delivery.

BACKGROUND: Bowen's disease (BD) is treated effectively with 5-aminolevulinic acid (ALA)-photodynamic therapy (ALA-PDT). Plum-blossom needling (PBN) may enhance topical drug delivery. OBJECTIVE: To compare the effects of and adverse reactions to PBN and ALA-PDT of BD with those associated with ALA-PDT alone. MATERIALS AND METHODS: Forty-three lesions from 24 patients were randomly assigned to 2 groups. The PBN-ALA-PDT group underwent vertical skin tapping with PBN before applying 10% ALA cream and narrow-band light-emitting diode irradiation (λ = 633 ± 10 nm; 100-200 J/cm). The ALA-PDT group received ALA cream and irradiation only. RESULTS: At 6 weeks, the PBN-ALA-PDT and ALA-PDT groups achieved complete response (CR) rates of 77.78% (14/18 lesions) and 40% (7/20 lesions), respectively, (p < .05), and 2/18 and 10/20 lesions, respectively, achieved CRs after further treatment; 2.9 ± 0.8 sessions and 3.4 ± 0.7 sessions, respectively, were required for the lesions to achieve CRs. The PBN-ALA-PDT group required fewer treatment sessions and had higher protoporphyrin IX fluorescence levels (p < .05). CONCLUSION: Plum-blossom needling may improve the efficacy of ALA-PDT by enhancing ALA delivery for BD treatment.

[Cytopenia under topical imiquimod in two patients treated with oral hydroxyurea]. / Cytopénies sous imiquimod topique chez deux patients traités par hydroxyurée.

BACKGROUND: Aldara® is a topical immunomodulatory treatment. The risks of systemic passage are minimal. There have been rare reports of systemic adverse effects. PATIENTS AND METHODS: Case 1. Five sachets weekly of imiquimod were prescribed for Bowen's disease on the forearm in a patient known to have essential thrombocytosis under Hydrea®. His CBC was normal (6000 leukocytes/mm3, 2200 PMN/mm, 230,000 platelets/mm3). Imiquimod was given in 15 sachets weekly. Fifteen day later, the patient presented bicytopenia (3000 leukocytes/mm3, 1400 PMN/mm3, 119,000 platelets/mm3). Hydroxyurea and imiquimod were suspended until normalization of CBC. Hydroxyurea was resumed without recurrence of the bicytopenia. The patient's history included an identical episode following application of imiquimod. Case 2. Five sachets weekly of imiquimod were prescribed for actinic keratosis on the scalp in a patient known to have primary polycythemia under hydroxyurea. Her CBC was normal except for anemia (Hb 11.5g/L, 160,000 platelets/mm3, 1100 lymphocytes/mm3). Imiquimod was given in 12 sachets weekly. Ten days later, anemia increased (Hb 10g/dL) with lymphopenia (800/mm3) and thrombocytopenia (115,000/mm3). Suspension of imiquimod resulted in normalization of the previous CBC values. DISCUSSION: . The literature review identified reports of dose-dependent lymphopenia under oral imiquimod but not under Aldara®. The National Pharmacovigilance Database listed 10 cases of hematological disorders most likely caused by Aldara®. Hydroxyurea may induce cytopenia, and while it was not considered the sole causative agent in this case, it is likely to have had a triggering role in these patients with blood dyscrasias. Our findings show that misuse of imiquimod carries a potential risk of hematologic abnormality in patients receiving concomitant hydroxyurea, a commonly combined drug.

Effectiveness of photodynamic therapy in Bowen's disease: a retrospective observational study in 423 lesions.

BACKGROUND: Photodynamic therapy (PDT) is a well-known technique that is often used for treating superficial precancerous and cancerous skin lesions. However, only a handful of studies, with a relatively small number of treated lesions, have been carried out on the effectiveness of PDT for Bowen's disease (BD). OBJECTIVES: This study aimed to assess the effectiveness and recurrence risk of PDT in the treatment of BD. The secondary objectives were to determine what factors affected the response rates and the cosmetic result of the treatment. METHOD: In this retrospective observational study, the electronic patient charts at Sahlgrenska University Hospital (SUH) in Gothenburg, Sweden, were searched to find all patients diagnosed with BD who were treated with PDT between 1 January 2002 and 31 December 2014. Data were collected regarding clinical response at the first follow-up visit, recurrences during later follow-up visits and other relevant patient and tumour characteristics. RESULTS: In total, 423 BD lesions in 335 patients were included in the study. The mean FU duration was 11.2 months (range 0.2-151 months). The complete response rate at the first FU visit was 77.5% for all BD lesions. During later FU visits, another 60 recurrences were observed, which resulted in a recurrence rate of 18.3%. Thus, the overall clearance rate after FU was 63.4% for all BD lesions. Significant risk factors for unsuccessful treatment in this study were large lesion size (>2 cm) and a single PDT session. CONCLUSION: This study shows that PDT is a relatively effective treatment modality for BD.

Treatment of Bowen Disease With Photodynamic Therapy and the Advantages of Sequential Topical Imiquimod. / Tratamiento de la enfermedad de Bowen con terapia fotodinámica y ventajas de la aplicación secuencial de imiquimod tópico.

Photodynamic therapy (PDT) has been shown to be useful and effective in the treatment of actinic keratosis, Bowen disease, and basal cell carcinoma. We present a series of 13 Bowen disease lesions treated using PDT. Complete responses were achieved in 11 (84%) of the lesions after 3 months of treatment; at 18 months, complete responses were seen in 9 (70%) of the lesions. Patients who presented a partial response or recurrence were treated with topical 5% imiquimod and achieved complete responses. The lesions that presented partial response or recurrence were the largest lesions, between 3 and 5cm in diameter. PDT in monotherapy or combined sequentially with imiquimod is an excellent and well-tolerated therapeutic option for Bowen disease. The treatment has few adverse effects and shows satisfactory results, particularly in multiple large lesions in areas of difficult surgical reconstruction or in elderly patients with a high surgical risk.

Linear porokeratosis with multiple squamous cell carcinomas successfully treated by electrochemotherapy.

Porokeratosis is a clonal epidermal disorder of keratinization characterized by annular lesions with an atrophic centre and a hyperkeratotic edge. The cornoid lamella is the histopathological hallmark. Six clinical variants are recognized: porokeratosis of Mibelli; disseminated superficial porokeratosis; disseminated superficial actinic porokeratosis (DSAP); porokeratosis plantaris et palmaris disseminata; punctate porokeratosis and linear porokeratosis. Linear porokeratosis is the type most frequently associated with malignant transformation into squamous cell carcinoma (SCC). It is thought to represent a mosaic form of DSAP and has an incidence of less than 1 in 200 000; treatment options are limited. We describe a patient with systematized linear porokeratosis and multiple SCCs who was successfully treated with bleomycin electrochemotherapy (ECT), a form of intralesional chemotherapy. In view of their large number, the individual SCCs were treated with bleomycin ECT. One year post-treatment the patient remains tumour free. To our knowledge, this is the first case of multiple SCCs treated by ECT in the context of systematized linear porokeratosis. Our case highlights the challenges associated with diagnosing and managing this unusual form of porokeratosis.