7. Therapy of squamous cell carcinoma in situ (Bowen's disease) – Actinic keratosis and squamous cell carcinoma of the skin

Background

The use of cryosurgery in the treatment of Bowen's disease is predominantly based on clinical experience. Our literature search identified two individual studies that investigated cryosurgery in a treatment arm [253][322]. Cryosurgery was investigated as a traditional, established, and widely used therapeutic modality in a comparison group to ALA or MAL-PDT. Studies comparing cryosurgery versus placebo as the primary study objective were not found. A systematic review also considered the above studies [323]. No RCT was found that investigated cryosurgery in immunosuppressed individuals.

Cryosurgery vs. MAL-red light PDT vs. placebo vs. 5-fluorouracil 5% cream

Population and study design: In 225 patients (87 men, 138 women aged 39-99), MAL-PDT was compared with placebo-PDT or with standard therapy (cryosurgery or 5-fluorouracil 5% cream) in a randomized, double-blind, placebo-controlled multicenter study [253]. Bowen's disease had to be previously histologically confirmed and with a lesion size of 6-40 mm. Randomization was into 4 groups: MAL-PDT (n=96 [124 lesions, of which 29 were localized to the head, 15 to the neck or trunk, and 80 to the extremities], mean age of 71.9 years [43-89], 36 men, 60 women), placebo-PDT (n=17 [24 lesions, of which 6 were localized to the head, 2 to the neck or trunk, and 16 to the extremities], mean age of 73.4 years [53-88], 6 men, 11 women), cryosurgery (n=82 [91 lesions, of which 26 were localized to the head, 13 to the neck or trunk and 52 to the extremities], mean age of 74 years [45-99], 34 men, 48 women) and 5-fluorouracil 5% (n=30 [36 lesions, of which 7 were localized to the head, 4 to the neck or trunk and 25 to the extremities], mean age of 72.5 years [39-86], 11 men, 19 women).

Intervention: Following superficial curettage of the lesions, MAL or placebo cream was applied 3 hours before exposure to a broadband red light source (570-670 nm, 75 J/cm2). One week after the first treatment, another PDT cycle was carried out. Cryosurgery was carried out with an open spray method as part of a spray/thaw cycle. Icing was carried out with a 2-mm margin beyond the lesion for at least 20 seconds. Cryosurgery was carried out only once. 5-Fluorouracil 5% cream was applied daily for the first week of treatment and twice daily for the following 3 weeks. Follow-up was carried out 12 weeks after therapy in all treatment groups. Lesions with a partial response (defined as reduction in lesion size ≥ 25% and < 100%) at this time point were treated again.

Results: Complete healing of lesions was seen in 93% (103/111) in the MAL-PDT group vs. 21% (4/19) in the placebo-PDT group vs. 86% (73/85) in the cryosurgery group vs. 83% (24/29) in the 5-FU group 3 months after the end of therapy. The lesion-related recurrence rate at 12 months was 15% (15/103) in the MAL-PDT group vs. 50% (2/4) in the placebo-PDT group vs. 21% (15/73) in the cryosurgery-PDT group vs. 17% (4/24) in the 5-FU group. A good or excellent cosmetic outcome at 3 or 12 months was observed in 94% for MAL-PDT, in 66% for cryosurgery, and in 76% for 5-FU. The frequency of the most commonly described adverse events can be seen in the table:

Assessment: In this study, patient- and lesion-related group characteristics were comparable at baseline. However, the risks for possible detection/performance and selection bias cannot be assessed with certainty.

Comparing the treatment modalities, MAL-PDT emerged as the most effective procedure in terms of complete healing of lesions (93%), with the lowest lesion-related recurrence rate (15%) at 12 months [253]. Thus, a significantly higher healing rate occurred under MAL-PDT compared with cryosurgery (relative risk 1.17; 95% CI 1.01-1.37) [323][323]; the differences in recurrence rates between the two procedures were not significantly different at 12 months (relative risk 0.71; 95% CI 0.37-1.36) [323]. The two comparators cryosurgery and 5-FU show comparable results, which should be negligible in practical application. In addition to the efficacy, the different profiles of adverse events as well as the cosmetic outcome are of particular importance; this latter was rated worst for cryosurgery with 66% in comparison.

Cryosurgery vs. ALA Red Light PDT

Population and study design: This randomized, 2-arm comparative study evaluated the treatment of 19 patients (3 men and 16 women) with a total of 40 lesions of Bowen's disease by ALA-PDT or cryosurgery at one study site [322]. The mean age of the patients was 76 [62-88] years. The 40 lesions were randomized 1:1 (n=20) into the two therapy arms with comparable locations (ALA-PDT group: legs [n=17], face [n=2] and hands [n=1] and cryosurgery group: legs [n=16], face [n=3] and hands [n=1]). Lesions were histologically confirmed by 4-mm punch biopsy before therapy and were therapy-naive. Only lesions with a diameter of ≤ 21 mm were included.

Interventions: ALA-PDT was carried out with a 20% ALA oil-in-water emulsion. For this, approximately 50 mg/cm² was applied to a lesion including a narrow margin of clinically healthy tissue and incubated for 4 hours under film occlusion. This was followed by exposure for 30 minutes at a flux rate of 70 mW/cm², resulting in a total dose per lesion of approximately 125 J/cm². A 300W xenon lamp was used as the light source, which emitted a broadband spectrum (30nm) in the 630nm range with appropriate filters.

Cryosurgery was carried out using an open spray method as part of a spray/thaw cycle. Icing was performed with a 2-3 mm margin beyond the lesion for at least 20 seconds.

Results: Complete healing of lesions was observed in 75% (15/20) after one session of ALA-PDT and in 100% (5/5) after another PDT session. In the cryosurgery group, complete healing of lesions was seen in 50% (10/20) after the first therapy, 80% (6/10) after the second therapy, and 100% (4/4) after a third cryosurgery. In each case, the differences after one or after a second cycle of therapy were not statistically significant (relative risk 1.50; 95% CI 0.90-2.49 and relative risk 1.24; 95% CI 0.98-1.57, respectively). The lesion-related recurrence rate showed one recurrence in each of the cryosurgery groups at 6 and 8 months, which healed after repeat cryosurgery. The authors reported complete healing at 12 months in 100% for ALA-PDT and in 90% (18/20) for cryosurgery. This is not statistically significant (Fisher's Exact Test: p=0.49). Pain was observed during therapy in the ALA-PDT group for 11 lesions (6 mild, 5 moderate) and in 19 lesions (12 mild, 7 moderate) in the cryosurgery group. For the cryosurgery group, in contrast to the ALA-PDT group (no other adverse events), ulcerations were still described in 5 lesions and infections in 2 lesions.

Assessment: In this study, ALA-PDT showed a significantly higher response after fewer cycles of therapy and no recurrences during the 12-month follow-up period compared with cryosurgery. It should be noted that lesions in the ALA-PDT group were significantly larger on average (150mm² [25-441mm²]) than lesions in the cryosurgery group (82mm² [30-360mm²]). The study showed that both therapeutic procedures required more cycles of therapy depending on increasing lesion size. ALA-PDT was also superior to cryosurgery in adverse events and painfulness. Critically, no statement can be made about possible influencing factors due to lack of data.

Background

One randomized trial was identified that compared CO₂ laser ablation with ALA red light PDT combined with CO₂ laser ablation [324].

Population and study design: The present randomized, controlled, double-blinded study examined the efficacy of ALA red light PDT after CO₂ laser therapy (PDT+ laser) and CO₂ laser ablation (laser) alone for Bowen's disease in an interindividual comparison at a study site [324]. 22 lesions in 18 patients (8 men and 10 women) with a mean age of 52 (35 - 72) years were randomized 1:1 (n=11 lesions each) into the two therapy groups. Histologically confirmed lesions had a mean diameter of 2.6±0.9 cm.

Interventions: All lesions were treated with 2-3 watts of power using a CO₂ laser under local anesthesia. The level of tissue vaporization was chosen at the level of the stratum papillare in hairless skin and at the level of the mid stratum reticulare in haired skin. The vaporized tissue was removed with a tissue. In the laser group, no further intervention was followed. In the PDT+ laser group, ALA red light PDT was performed immediately afterwards. This was carried out with a 20% ALA emulsion. ALA was applied beyond the lesion with a margin of clinically healthy skin of 0-4 mm and incubated for 5 hours under foil occlusion. Subsequently, exposure was at a flux rate of 100 mW/cm², resulting in a total dose per lesion of approximately 180 J/cm². The light source used was a laser emitting a wavelength of 630nm.

Lesions were evaluated clinically at 1 and 4 weeks after therapy. If healing was not complete, therapy was repeated no later than 4 weeks after the previous therapy. If healing was not achieved after 3 cycles, the lesion was surgically removed. Histological controls of therapy were carried out 1 month and 6 months after the last cycle.

Results: There was better complete lesion healing in the PDT+ laser group with 72.7% (8/11) compared to the laser group with 63.3% (7/11). Overall, more healings (overall clearance) were observed in the PDT+ laser group with 90.9% (10/11) compared to 54.6% (6/11) in the laser group. The recurrence rate at 6 months was significantly better in the PDT+ laser group at 9% (1/11) compared to 45.5% (5/11) in the laser group. Patient satisfaction was higher in the PDT+ laser group at 80% (8/10) compared with 62.5% [5/8] in the laser group. Adverse events reported for the PDT+ laser group were redness, swelling, and stinging and burning sensations. In the laser group, in addition to mild to moderate swelling and erosion, delayed healing occurred in 2 patients, prolonged pain in 2 patients, ulceration in 3 patients and scarring in 2 patients.

Evaluation: A combination of CO₂ laser ablation followed by ALA-PDT with red light is superior to CO₂ laser ablation alone in both healing rate and recurrence frequency. However, this is a small study population, so the results should be evaluated with caution. The extent to which this combination is actually useful after the entire epidermis has been vaporized with the laser is questionable for several reasons. Among others, with laser ablation at the described penetration depth, Bowen's disease should already have been removed and no vital keratinocytes needed for PDT should still be present. Therefore, laser ablation alone is suitable as an optional procedure.

Background

5-Fluorouracil (5-FU) is a cytostatic drug. The pharmacologically active component of 5-FU, 5-fluorodeoxyuridine monophosphate, is an antimetabolite that prevents the methylation of deoxyuridine monophosphate to deoxythymidine monophosphate by inhibiting thymidylate synthase. This leads to thymidine deficiency, which impairs DNA synthesis and RNA transcription. Although this affects proliferatively active cells more than normal keratinocytes, the mechanism of action of 5-FU is thus non-specific. It is metabolized predominantly by the enzyme dihydropyrimidine dehydrogenase (DPD). Patients with reduced activity of this enzyme may experience decreased degradation with the risk of severe local or even systemic side effects. In addition, DPD activity is impaired by viral nucleoside analogues such as brivudine. Severe side effects have also been observed with concomitant, systemic administration of methotrexate. In Germany, 5-FU is approved as a 5% cream for the treatment of Bowen's disease. It is applied twice daily for a maximum of 4 weeks. After 1-2 weeks, initial treatment effects such as redness or erosion are usually observed. The systematic literature search revealed 3 single studies [325][326][253] and 1 systematic review [323] that investigated 5-FU in the concentration 5%.

5-Fluorouracil 5% cream vs. MAL red light PDT vs. cryosurgery vs. placebo

For more detailed information comparing these interventions, see here.

Assessment: There was no significant difference in lesion-related healing comparing 5-FU and MAL-PDT (relative risk 1.16; 95% CI 0.93-1.44) or 5-FU and cryosurgery (relative risk 0.99; 95% CI 0.78-1.26) [253][323]. There was also no significant difference in recurrence rate at 12 months comparing both 5-FU and MAL-PDT (relative risk 0.59; 95% CI 0.31-1.13) and 5-FU and cryosurgery (relative risk 1.48; 95% CI 0.53-4.17) [323]. In the adverse event comparison, significantly more events were seen in the 5-FU group compared with both the cryosurgery group (relative risk 0.64; 95% CI 0.47-0.86) and the MAL-PDT group (relative risk 0.26; 95% CI 0.08-0.80) [323].

5-fluorouracil 5% cream vs. ALA-red light-PDT

Population and study design: This randomized, 2-arm comparative study evaluated the treatment of 40 patients (8 men and 32 women) with a total of 66 lesions of Bowen's disease by ALA-PDT or 5-fluorouracil cream 5% at one study site [326]. The mean age of the patients was 76 [65-88] years. The 66 lesions were randomly assigned in a 1:1 ratio (n=33) and were localized exclusively to the legs (n=33) in the ALA-PDT group and to the majority of the legs (n=22) and to the arms (n=4) and face (n=4) in the 5-FU group. The lesions were histologically confirmed before therapy, had existed for at least 6 months, and were therapy-naive. Per patient, 1-3 lesions were treated, ranging in size from 0.5-4.0 cm in diameter.

Interventions: ALA-PDT was carried out with a 20% ALA oil-in-water emulsion. ALA was applied beyond the lesion with a margin of clinically healthy skin of at least 5 mm and incubated for 4 hours under film occlusion. Then, depending on lesion size, exposure was between 12-40 minutes at a flux rate of 50-90 mW/cm², resulting in a total dose per lesion of approximately 100 J/cm². A 300W xenon lamp was used as the light source, which emitted a broadband spectrum (± 15nm) in the 630nm range with appropriate filters. The 5-fluorouracil cream 5% was applied thinly to the lesion once daily during the first week of treatment. In weeks 2-4, application was twice per day.

Results: Significantly more (relative risk 1.83; 95% CI 1.10-3.06) lesion-related healings were observed in the ALA-PDT group at 88% (29/33) than in the 5-FU group at 67% (22/33) [323][326]. The recurrence rate was not significantly different with 2 lesions in the ALA-PDT group and 6 lesions in the 5-FU group (relative risk 0.33; 95% CI 0.07-1.53) [323][326]. Thus, the authors report a significantly better complete cure rate at 12 months of 82% (27/33) for ALA-PDT compared to 48% (16/33) for 5-FU (p=0.006, OR 4.78; 95% CI 1.56-14.62) [326].

Significantly fewer (0/33) adverse events (including eczema reactions and ulcerations) were observed in the ALA-PDT group than in the 5-FU group (12/33) (Fisher's Exact Test: p < 0.001) [323][326]. Compared with ALA-PDT, scarring occurred in 3 reported ulcerations in the 5-FU group. Differences in terms of treatment-related pain were not reported.

Assessment: In immunocompetent patients, ALA-PDT is superior to 5-FU in terms of complete healing after 12 months and side effect profile. Due to the lack of data, no conclusive assessment of possible influencing factors is possible. Women were clearly overrepresented in the study population (32 to 8).

5-Fluorouracil 5% cream vs. MAL red light PDT (immunosuppressed)

Population and study design: In 8 organ transplant recipients (kidney transplant [n=7] and combined liver/kidney transplant [n=1]) with immunosuppression (6 men, 2 women, mean age 59 [46-71] years), the efficacy of 5% 5-FU cream vs MAL red-light PDT was compared intra-individually at one study site as part of an "open-label“- study. Transplants had taken place on average 20 (11-30) years ago. A total of 8 AK and 10 lesions of Bowen's disease were treated in the intervention study. The evaluation was done after 1, 3 and 6 months. No other therapy was allowed in these areas for 8 weeks prior to therapy and the diagnosis of the lesions were confirmed histologically. Lesion sizes ranged from 39-5010 mm² [325].

Interventions: For PDT, MAL cream (160mg/g) was applied approximately 1 mm thick and incubated for 3 hours under foil occlusion. Encrusted lesions were carefully curetted beforehand. Subsequently, exposure to red light (633 ± 15 nm) was carried out at a flux rate of 80 mW/cm², resulting in a total dose per lesion of 75 J/cm². The procedure was repeated after 1 week regardless of the findings.

5-FU cream 5% was applied to the lesions twice daily for 3 weeks. Again, crusted lesions were carefully curetted at baseline.

Results: At all 3 observation time points, MAL-PDT showed significantly better complete treatment response with 89% (8/9) compared to 11% (1/9) with 5-FU (p=0.02) [325]. The mean reduction in lesion area was also greater for MAL-PDT compared to 5-FU (100% vs. 79%). The cosmetic outcome was better after MAL-PDT and was rated excellent in 100%. The difference was not statistically significant (Fisher's Exact Test: p=0.08) [325]. Patient preference was also in favor of MAL-PDT. Adverse events reported were crusts, itching and hyperpigmentation for MAL-PDT and superficial erosions, crusts and itching for 5-FU. Pain during therapy was higher with MAL-PDT than with 5-FU use.

Assessment: In immunosuppressed individuals, MAL-PDT is significantly superior to topical 5-FU application in terms of complete healing rate at all observation time points. None of the patients experienced a deterioration of renal function during the study period. Overall, however, the present study population is quite small. Due to the lack of data, it is not possible to make a conclusive assessment of possible influencing factors.

Background

The specific toll-like receptor (TLR) 7 agonist imiquimod 5% has been approved since 2006 for the topical treatment of clinically typical, non-hyperkeratotic, non-hypertrophic AK (Olsen grade I to II) on the face or scalp and for the treatment of small superficial basal cell carcinoma in immunocompetent adults. It is available as a cream portioned in individual sachets (12.5 mg), which is the maximum dose per treatment day. Imiquimod 5% cream should be applied to a maximum treatment area of 25 cm² three times weekly for 4 weeks each time for therapy of AK and left on the skin for approximately 8 hours. After a four-week treatment-free period, the healing of the AK should be checked and, if necessary, a second treatment cycle over 4 weeks should follow. In the treatment of superficial basal cell carcinoma, the cream is applied to the corresponding lesion 5 times/week (Mon-Fri) for 6 weeks and left for 8 hours. 12 weeks after the end of therapy, the result should be assessed. In case of therapy failure, no further cycle should be carried out and another therapy procedure should be chosen.

Treatment of Bowen's disease using imiquimod 5% is equivalent to off-label use.

Imiquimod 5% cream vs. placebo

Population and study design: In this randomized, double-blinded study, imiquimod 5% cream vs. placebo was evaluated in the treatment of histologically confirmed Bowen's disease at one center. For this purpose, out of a total of 31 patients (11 men and 20 women), 16 patients (2 men and 14 women) with a mean age of 74 (60-86) years were randomized to the placebo group and 15 patients (9 men and 6 women) with a mean age of 74 (54-83) years were randomized to the imiquimod 5% group. In the placebo group, the mean lesion size was 248 (84-555) mm² and in the imiquimod 5% group it was 429 (23-1776) mm² [327].

Interventions: Both imiquimod 5% cream and placebo cream were applied to the lesions by patients 1x daily for 16 weeks. Patients were allowed to discontinue therapy a maximum of twice during the study for a maximum of 5 consecutive days if the inflammatory response was subjectively too severe. Evaluation was done at week 28 (12 weeks after end of therapy).

Results: In the imiquimod 5% group, 75% of patients (9/15) showed complete healing of lesions compared to 0% in the placebo group (Fisher's Exact Test: p< 0.001). The mean decrease in lesion size between week 0 and week 28 was statistically significantly greater (p=.041) in the imiquimod 5% group at -322 mm² (±519 mm²) than in the placebo group at -37 mm (±114 mm²). It should be mentioned that a total of 3 patients (all in the imiquimod 5% group) did not complete the study. No recurrences were reported in a follow-up at 9 months. In the imiquimod 5% group, almost all patients showed a localized inflammatory reaction. Overall, 19 of the 31 patients had transient itching, swelling, as well as oozing of the lesion.

Assessment: Due to the small number of patients, a reliable statement on the efficacy of imiquimod 5% for the treatment of Bowen's disease is difficult, especially in comparison to other therapies. Imiquimod 5% was superior to placebo. However, it must be noted that the application regimen (1x daily for 16 weeks) in this study did not correspond to any approved application (neither for AK nor for superficial basal cell carcinoma). The application duration was longer and more frequent. In addition, the characteristics of the two study groups at baseline were significantly different, particularly with regard to lesion sizes.

Classic formulations of ALA in creams, gels, solutions or ointments are not very stable and are rapidly degraded in the skin microenvironment. In addition, ALA is somewhat more hydrophilic than MAL and therefore has relatively poorer penetration properties, especially in thicker, hyperkeratotic lesions. In Germany, conventional ALA mixtures are available only as individual prescriptions or extemporaneous preparations (R007). The nanoemulsion approved since 2012 for the therapy of AK, which corresponds to a 10% ALA preparation (BF-200 ALA), has no explicit approval for the therapy of Bowen's disease. 

The studies identified in the literature search [322][326][326][324][328][326][332], investigating ALA-PDT for the treatment of Bowen's disease include small collectives (median lesion number treated with ALA-cPDT: n=33 [11-61]). In particular, the studies are heterogeneous in terms of treatment protocols (timing and frequency of PDT cycles), light sources used, ALA formulations, and endpoints reported. Therefore, comparison of results is not possible. The range of complete lesion healings achieved also varies widely, with results ranging from 40% to 94% [328][332]. In principle, with regard to the analyzed studies on MAL-PDT, it would be reasonable to follow the established procedure of 2 therapy cycles at an interval of 1 week with an incubation period of 3 hours and exposure to a narrow spectrum red light.

ALA-PDT with red light vs. green light

Population and study design: The randomized comparative study by Morton et al. evaluated the efficacy of ALA-PDT with red (rPDT) versus green (gPDT) light in 16 patients with a mean age of 73 (50-87) years and a total of 61 histologically confirmed lesions at one study site [328]. Patients had a median of 3 (1-6) lesions, all of which were localized to the legs. 29 lesions with a median treatment area of 125 (16-441) mm² were randomized to the gPDT group and 32 lesions with a median treatment area of 100 (25-400) mm² to the rPDT group. Lesions were all treatment-naive and had a diameter of ≤ 21 mm.

Interventions: ALA-PDT was carried out with a 20% ALA oil in water emulsion. Prior to this, crusts were gently curetted. Approximately 50 mg/cm² ALA was applied beyond the lesion with a margin of clinically healthy skin of at least 4 mm and incubated for 4 hours under film occlusion. This was followed by exposure to either green (gPDT group) or red (rPDT group) light. A 300W xenon lamp was used as the light source, emitting an adapted spectrum of 540±15 nm (green) or, with appropriate filters, a spectrum of 630 nm±15 nm (red). With a flux rate of 86 mW/cm², lesions in the rPDT arm received a total dose of 125 J/cm² and lesions in the gPDT arm received a total dose of 62.5 J/cm². The different total dose was chosen under the notion that approximately twice as much protoporphyrin IX is formed with green light exposure (540 nm) as with red light exposure (630 nm). Clinical follow-up was carried out 2 months after therapy. If healing was not complete, the therapy was repeated once. Subsequently, monthly clinical controls were carried out for 12 months. In case of clinical doubt, a biopsy was taken for histological examination.

Results: The lesion-related healing rate was 94% (30/32) in the rPDT group and 72% (21/29) in the gPDT group (p=0.002). At 12 months, 74% fewer recurrences (88% [2/32]) were observed in the rPDT group than in the gPDT group (48% [7/29]) (relative risk 0.26; 95% CI 0.06-1.15) [323][328]. The occurrence and severity of pain during therapy was comparable in both groups (relative risk 1.09; 95% CI 0.79-1.49) [328][323].

Assessment: ALA-PDT with red light is superior to ALA-PDT with green light in terms of lesion-related healing rate and recurrence rate at 12 months. It should be noted that the risk of influence on the results is not comprehensible due to, among other factors, lack of blinding and that the study population was comparatively small.

ALA-PDT vs. cryosurgery

See see

ALA-PDT vs. 5-fluorouracil 5% cream

See See

ALA-PDT combined with microneedling vs. ALA-PDT alone

Population and study design: The prospective, controlled-randomized study by Wu et al. compared the efficacy of conventional ALA-PDT with pretreatment needling (PDT+) and ALA-PDT alone (PDT) for Bowen's disease at one study site [332]. For this purpose, of 43 lesions in 24 Asian-origin patients (12 men and 12 women) with a mean age of 55.5±10 years, 21 lesions were randomized to the PDT+ group and 22 lesions to the PDT group. In the PDT+ group, the mean lesion diameter was 2.5 ± 1.0 cm and in the PDT group, 2.6 ± 1.2 cm. Three lesions were excluded in the PDT+ group and 2 lesions were excluded in the PDT group, resulting in 18 lesions for the PDT+ and 20 lesions for the PDT group in the final evaluation.

Interventions: In the PDT+ group, lesions were pretreated with a "plum-blossom needling tool“. This is a small, hammer-like tool with 7 needles that are 4 mm long, 0.5 mm thick, and placed 4 mm apart on the surface. This is the reason for its name (plum blossom). For pretreatment of the lesions, the lesions were tapped vertically from a distance of approximately 5 cm until bleeding occurred. Before carrying out PDT, the resulting encrustations were removed.

Subsequently, a 10% ALA cream was applied beyond the lesion with a margin of clinically healthy skin and incubated for 3 hours under film occlusion. This was followed by exposure to a narrow spectrum LED (633±10 nm) at a flux rate of 60-150 mW/cm², resulting in a total dose per lesion of 100 to 200 J/cm². The same exposure protocol was carried out in the PDT group but without pretherapy.

If healing was not complete, therapy was repeated up to 6 times. If complete healing of a lesion was not achieved even after 6 cycles, it was excised. After complete healing, monthly clinical controls were carried out for 12 months.

Results: Six weeks after therapy, a significantly higher (p< 0.05) complete lesion healing of 77.8% (14/18) was observed in the PDT+ group compared to 40% (7/20) in the PDT group. After further cycles of therapy, 11.1% (2/18) in the PDT+ group and 50% (10/20) in the PDT group still showed complete lesion-related healing. In the PDT+ group an average of 2.9±0.8 therapy cycles and in the PDT group 3.4±0.7 cycles were required to achieve complete lesion-related healing. The recurrence rate at 12 months was 0% in the PDT+ group and 11.8% in the PDT group (2/17). The two procedures did not differ with regard to the painfulness of the treatments (pain score in both groups of 4.5) and the observed PDT-typical adverse events.

Assessment: Pretreatment with a "plum blossom needling tool“ in combination with red light ALA-cPDT compared to red light ALA-cPDT alone showed higher efficacy and lower recurrence rates with comparable adverse event profiles. Overall, however, the results are based on a small sample size and the results are explicitly assumed to be only for people of Asian descent. Sources of error may be possible, for example, due to unreported blinding or non-selective reporting of adverse events for each study arm.

ALA-PDT combined with CO₂ laser ablation vs. CO₂ laser ablation alone

See See chapter Ablative laser procedures

MAL is approved in combination with red light for topical PDT of Bowen's disease in immunocompetent adults. It is available as a cream (1 g cream contains 160 mg methyl (5-amino-4-oxopentanoate) as hydrochloride) and, in the case of red light PDT, is applied to the lesion site and surrounding area (5-10 mm border) with a layer thickness of 1 mm after lesion pretreatment (removal of scales and crusts and roughening of the surface). After an exposure time of 3 hours under a light-tight occlusive dressing and wiping off excess ointment residues, illumination with red light (continuous wavelength spectrum between 570 and 670 nm and a total light dose of 75 J/cm²; alternatively, narrow-spectrum light (e.g., by means of LED lights around 630 nm) can be used, with adjustment of the light dose (usually 37 J/cm²)). Due to selective porphyrin synthesis in the abnormal keratinocytes of Bowen's disease, illumination causes a localized phototoxic reaction resulting in necrosis and apoptosis. This is a twice-daily treatment that should be given 1 week apart. According to the regulatory text "there is no experience treating Bowen's disease lesions larger than 40 mm. As with the treatment of Bowen's disease by cryotherapy or with 5-FU, the response rate of large lesions (> 20 mm in diameter) is lower than for small lesions.“ There is no approval in combination with natural daylight or daylight-emitting lamps (simulated daylight).

The studies identified in the literature search [253][329][330][331] investigating MAL-PDT in immunocompetent individuals for the treatment of Bowen's disease include small collectives (median number of lesions treated with MAL-PDT: n=71 [6-96]). These studies use the same PDT protocol for conventional red-light PDT, with 3 of the studies using a narrow-spectrum light source [329][330][331] and only one study [253] (closest based on study timing) using a broad-spectrum light source. The range of complete lesion healings achieved varied from 73% to 93% [253][331] and could be improved by pre-therapy with a fractional Er:YAG laser [330][331].

MAL-PDT vs 5-fluorouracil 5% cream vs cryosurgery vs placebo

For more detailed information comparing these interventions, see see.

MAL-PDT vs. 5-fluorouracil 5% cream (immunosuppressed)

For more detailed information comparing these interventions, see see.

MAL-PDT combined with fractional Er:YAG laser vs. MAL-PDT alone.

Population and study design: The two studies by Ko et al. [331] and Kim et al. [330] investigate the efficacy of MAL-red light-PDT combined with fractionated Er:YAG-laser pre-therapy versus MAL-red light-PDT without pre-therapy for Bowen's disease at the lower extremities in Asian-descended collectives at one study center each. For this, Ko chooses an intra-individual comparison with double blinding and Kim chooses an inter-individual comparison approach with single blinding of the assessing subject.

In the study by Ko et al. [331], the patient population consisted of 21 patients (10 men and 11 women) with a mean age of 68.9 (35-88) years and at least 2 (n=58) histologically confirmed Bowen's disease lesions. Of the lesions, 32 were randomized to the fractionated laser pre-therapy (AFL-PDT) group and 26 lesions to the MAL-PDT alone group.

In the study by Kim et al. [330], 60 patients (30 each male and female) with a total of 84 Bowen's disease lesions were randomized 1:1 to the AFL-PDT and MAL-PDT groups. The AFL-PDT group consisted of 13 men and 17 women with a mean age of 71.8 ±12.6 years and 46 lesions with a mean lesion diameter of 11.6 ±7.0 mm. The Mal-PDT group was composed of 11 men and 19 women with a mean age of 69.9 ±13.1 years and 38 lesions with a mean lesion diameter of 13.2 ±6.4 mm.

Interventions: In both studies, pretherapy (AFL) was performed after gentle, bleed-free curettage of possible crusts and analgesia using a 30-minute application of 5% lidocaine-priolocaine cream with a fractional Er:YAG laser (2940 nm) at a penetration depth of 550-600 nm, level 1 coagulation, 22% therapy density, and single pulses. Immediately following, MAL cream (160mg/g) was applied approximately 1 mm thick beyond the lesion with a margin of clinically healthy skin of 5 mm and incubated for 3 hours under foil occlusion. Exposure was then to a narrow spectrum LED red light (632 nm) with a total of 37 J/cm². In the MAL-PDT study arm, PDT was carried out exactly the same after successful hemorrhage-free curettage. The procedures were repeated after 1 week regardless of the findings. Follow-up was carried out at 3 and 12 months after therapy. In the study by Kim et al., even 5-year data were collected [330].

Results: In the work of Ko et al. [331], the AFL-PDT group showed lesion-related complete healing of 93.8% (30/32) vs. 73.1% (19/26) at 3 months (p=0.031) and 87.5% (28/32) vs. 50% (13/26) at 12 months (p=0.002) compared to the MAL-PDT group alone. The study by Kim et al. [330] showed comparable rates for the two groups of 93.5% (43/46) vs. 76.3% (29/38) at 3 months (p=0.034), 87.0% (40/46) vs. 55.3% (21/38) at 12 months (p=0.002) and 84.8% (39/46) vs. 44.7% (17/38) at 5 years (p< 0.001). The recurrence rate at 12 months for the two groups (AFL-PDT vs. MAL-PDT) also showed comparable results in the two studies with 6.7% vs. 31.6% (p=0.022) in the work of Ko et al. [331] and 7.0% vs. 27.6% (P=0.033) and 9.3% vs. 41.4% (p=0.003), respectively, at 5 years in the work of Kim et al. [330]. In addition, the study by Kim et al. identified lesion diameter > 20 mm and previous other therapies of the respective lesion as two independent factors of treatment failure [330].

Both studies showed the following adverse events in the AFL-cPDT group compared to the MAL-PDT alone group.

Ko et al. [331]: erythema (94.4% vs. 88.9%), crusts (100% vs. 100%), hyperpigmentation (66.7% vs. 55.6%), itching (27.8% vs. 22.2%), burning sensations (83.3% vs. 72.2%), and pain on a VAS (4.9±2.0 vs. 4.3±1.8). Comparable good or excellent cosmetic outcome of both treatment arms is reported in this study.

Kim et al. [330]: erythema (93% vs. 90%), crusts (80% vs. 80%), hyperpigmentation (76% vs. 70%), itching (70% vs. 67%), burning sensations (73% vs. 67%), and pain on a VAS (6.1±1.0 vs. 5.6±1.3).

Assessment: In both studies, complete lesion-related healing with fractionated Er:YAG laser pre-therapy was statistically significantly superior to MAL-PDT alone across all time points. This was especially true for the long-term data of 5 years (85% vs. 45%). The recurrence rate is also shown to be comparable in both studies and statistically significantly lower for the pretreated lesions, although again, the values at 5 years (9.3% vs. 41.4% recurrences) should be noted in particular.

Even though these two studies represent the largest comparative collectives for PDT in Bowen's disease, they must be considered rather small in relation to the frequency of the disease. Furthermore, the subject collectives are formed by predominantly Asian-origin (Korean) patients with a skin type mean of III-IV according to Fitzpatrick and are limited to the lower extremity. Therefore, a transfer of the results to other localizations or a Caucasian patient collective should be considered at least with caution.

MAL-PDT combined with continuous vs. fractional CO₂ laser

Population and study design: The randomized, controlled, intra-individual comparative study by Genouw et al. investigated the efficacy of continuous versus fractionated CO₂ laser therapy for MAL-cPDT in 15 patients (7 men and 8 women) with a median age of 73 (46-87) years and a total of 6 inoperable, histologically confirmed Bowen's disease lesions at a study site [329]. Lesions were either > 5 cm², which were then divided into 2 equal-sized study areas, or patients had 2 comparable-sized lesions. Because superficial basal cell carcinomas were investigated in addition to Bowen's disease in this study, the locations of each Bowen's disease lesion were not reported separately.

Interventions: The lesions were either pretreated in half or the 2 comparable lesions were each pretreated differently. One group received continuous CO₂ laser therapy (CL) with a pulse duration of 8 ms at a power of 12 W, so that ablation to the level of the papillary dermis was achieved. The other study arm received fractional CO₂ laser therapy (FL) at a power of 30 W (15% density, 18µm spot size, 240mJ energy, and a flow rate of 943 J/cm²). In case of hemorrhage, 20% ferric chloride was used to stop bleeding. For subsequent PDT, MAL cream (160mg/g) was applied approximately 1 mm thick and incubated for 3 hours under foil occlusion. Exposure was with a narrow spectrum LED red light with a total of 37 J/cm². The procedure was repeated after 2 weeks regardless of the findings. Assessments were made for complete healing (100%), partial healing (25-99%), and nonresponse (0-24%). Clinical assessments were also confirmed histologically (punch biopsy). Corresponding follow-up examinations were carried out at 3, 6 and 12 months after the second cycle of therapy.

Results: At 12 months, both study arms (FL and CL) showed the same complete lesion-related healing rate of 80% (4/5). PDT-typical adverse events as well as cosmetic outcome was also the same in both groups. Regarding painfulness (including basal cell carcinomas), the second therapy was shown to be more painful (p=0.026) in the CL group compared to the FL group.

Conclusion: There are no differences in efficacy (80% CR at 12 months) and side effect profile between continuous and fractional CO₂ laser therapy before MAL-PDT. Only painfulness appeared to be less with fractionated laser pre-therapy at a second cycle than with continuous. Overall, however, the study population is very small (n=5 at 12-month follow-up), so the robustness of the results obtained is highly questionable. Furthermore, except for complete lesion healing, no results were reported separately by study arm and entity (basal cell carcinoma vs. Bowen's disease).