Photodynamic therapy with topical methyl aminolaevulinate for 'difficult-to-treat' basal cell carcinoma

BACKGROUND: Basal cell carcinoma (BCC) may be difficult to treat by conventional means, particularly if the lesions are large or located in the mid-face (H-zone). Photodynamic therapy (PDT) using topical methyl aminolaevulinate (MAL) may be a good noninvasive option for these patients. OBJECTIVES: To investigate the efficacy and safety of PDT using MAL for BCCs defined as 'difficult to treat', i.e. large lesions, in the H-zone, or in patients at high risk of surgical complications. METHODS: This was a prospective, multicentre, noncomparative study. Patients were assessed 3, 12 and 24 months after the last PDT treatment. One hundred and two patients with 'difficult-to-treat' BCC were treated with MAL PDT, using 160 mg g(-1) cream and 75 J cm(-2) red light (570-670 nm), after lesion preparation and 3 h of cream exposure. Results Ninety-five patients with 148 lesions were included in the per protocol analysis. The histologically confirmed lesion complete response rate at 3 months was 89% (131 of 148). At 12 months, 10 lesions had reappeared, and therefore the cumulative treatment failure rate was 18% (27 of 148). At 24 months, an additional nine lesions had reappeared, resulting in a cumulative treatment failure rate of 24% (36 of 148). The estimated sustained lesion complete response rate (assessed using a time-to-event approach) was 90% at 3 months, 84% at 12 months and 78% at 24 months. Overall cosmetic outcome was judged as excellent or good in 79% and 84% of the patients at 12 and 24 months, respectively. Follow-up is continuing for up to 5 years. CONCLUSIONS: MAL PDT is an attractive option for 'difficult-to-treat' BCC. Because of the excellent cosmetic results, the treatment is particularly well suited for lesions that would otherwise require extensive surgical procedures.     

Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment

Background Conventional treatment of basal cell carcinoma (BCC) causes morbidity and/or disfigurement in some patients because of the location (e.g. mid‐face) and size of the lesion. Objectives Following reports that such difficult‐to‐treat BCC lesions have been treated successfully with topical methyl aminolaevulinate (MAL) photodynamic therapy (PDT), a multicentre study was performed to determine the response of such BCC to MAL‐PDT. Methods An open, uncontrolled, prospective, multicentre study was conducted comprising patients with superficial and/or nodular BCC who were at risk of complications, poor cosmetic outcome, disfigurement and/or recurrence using conventional therapy. Patients were given one or two cycles within 3 months of topical MAL‐PDT, each consisting of two treatments 1 week apart. Tumour response was assessed clinically at 3 months after the last PDT, with histological confirmation of all lesions in clinical remission. The cosmetic outcome was rated. Patients with a BCC in remission will be followed up for 5 years for recurrence, of which the 24‐month follow‐up is reported here. Ninety‐four patients with 123 lesions were enrolled and treated with MAL‐PDT at nine European primary care and referral university hospitals. An independent blinded study review board (SRB) retrospectively excluded nine patients and a total of 15 lesions from the efficacy analysis, for not having a difficult‐to‐treat BCC according to the protocol. Results The lesion remission rate at 3 months was 92% (45 of 49) for superficial BCC, 87% (45 of 52) for nodular BCC, and 57% (four of seven) for mixed BCC, as assessed by clinical examination, and 85% (40 of 47), 75% (38 of 51), and 43% (three of seven), respectively, as assessed by histological examination and verified by the SRB. At 24 months after treatment, the overall lesion recurrence rate was 18% (12 of 66). The cosmetic outcome was graded as excellent or good by the investigators in 76% of the cases after 3 months follow‐up, rising to 85% at 12 months follow‐up, and 94% at 24 months follow‐up. Conclusions Topical MAL‐PDT is effective in treating BCC at risk of complications and poor cosmetic outcome using conventional therapy. MAL‐PDT preserves the skin and shows favourable cosmetic results.     

Treatment of superficial basal cell carcinoma by topical photodynamic therapy with fractionated 5‐aminolaevulinic acid 20% vs. two‐stage topical methyl aminolaevulinate: results of a randomized controlled trial

Photodynamic therapy (PDT) is a frequently used treatment for a type of skin cancer called superficial basal cell carcinoma (sBCC). It works by using a cream called a porphyrin precursor, which is applied to the affected skin area and covered with a dressing. After several hours and after removing the occlusive dressing, the area is irradiated with intense visible light which causes the death of cancer cells. There are two porphyrin precursors available in the Netherlands, 5‐aminolevulinic acid 20% (ALA) and methylaminolevulinic acid (MAL). In conventional MAL PDT, skin receives one illumination (treatment with light) which is repeated one week later. In the case of ALA, skin receives two different illuminations, two hours apart. This is called fractionated ALA‐PDT. In this study, from the Netherlands, we investigated whether this fractionated ALA‐PDT is superior to conventional MAL‐PDT. 162 patients were randomly assigned to one of two groups. 82 patients were treated with fractionated ALA‐PDT and 80 patients with conventional MAL‐PDT. After 12 months a total of 6 treatment failures (recurrence of the sBCC) occurred after ALA‐PDT and 13 after MAL‐PDT. Although there were twice as many treatment failures in the MAL‐PDT group, this difference was not statistically significant. Secondly, we investigated pain scores in both treatment groups because PDT is known to cause a severe burning sensation. We found that ALA‐PDT resulted in more pain and side effects, such as erythema (skin redness, like sunburn), wounds/erosions and vesicles (small blisters) compared to MAL‐PDT. In conclusion, there is a trend toward better efficacy of ALA‐PDT compared to MAL‐PDT for the treatment of sBCC, although the difference was not significant.     

Topical methyl aminolaevulinate photodynamic therapy for treatment of facial acne vulgaris: results of a randomized, controlled study

BACKGROUND: There is a need for alternative treatments for moderate to severe acne vulgaris. Preliminary experience suggests that topical methyl aminolaevulinate photodynamic therapy (MAL-PDT) may have potential. OBJECTIVES: To investigate the efficacy and tolerability of MAL-PDT for treatment of moderate inflammatory facial acne. PATIENTS/METHODS: Thirty patients aged 15-28 years with moderate to severe acne were included in a blinded, prospective, randomized, placebo-controlled multicentre study. Each side of each patient's face was randomly assigned to treatment with MAL (160 mg g1) or placebo cream, applied for 3 h prior to illumination. A second treatment was given 2 weeks later. On each occasion, patients assessed the intensity of pain using a 10-cm visual analogue scale. Inflammatory and noninflammatory acne lesions were counted at baseline and 4 and 10 weeks after the last PDT treatment. The investigator assessed the global severity of acne at baseline (seven patients had severe acne on at least one side of the face) and each study visit using a six-point rating scale. Data were analysed on an intention-to-treat basis, including all 30 patients. RESULTS: There was a statistically significant greater reduction in the total inflammatory lesion count with MAL-PDT compared with placebo PDT at week 12; median reduction 54% [95% confidence interval (CI) 35-64%] vs. 20% (95% CI 8-50%), P = 0.0006. MAL-PDT was associated with more pain than placebo PDT, although intensity varied across centres and was reduced with repeated treatment. Local adverse events were consistent with this treatment modality. CONCLUSIONS: MAL-PDT is effective in the treatment of moderate to severe inflammatory facial acne. Further studies are warranted to optimize this promising procedure.     

Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma

OBJECTIVE: To compare 5-year lesion recurrence rates in primary nodular basal cell carcinoma treated with topical methyl aminolevulinate photodynamic therapy (PDT) or simple excision surgery. DESIGN: Prospective, randomized, multicenter study. SETTING: University hospital dermatology departments. PATIENTS: A total of 97 patients, 50 with 53 lesions treated with methyl aminolevulinate PDT and 47 with 52 lesions treated by excision surgery, were included in the per protocol analysis. Of the lesions treated with methyl aminolevulinate PDT and surgery, 49 and 52, respectively, showed complete clinical response at 3 months after treatment and were observed for long-term outcome evaluation. INTERVENTIONS: Topical methyl aminolevulinate cream, 160 mg/g, applied for 3 hours before illumination (75 J/cm(2) of red light at 570 to 670 nm) on 2 or 4 occasions (12 [23%] of 53 lesions); or excision surgery. MAIN OUTCOME MEASURES: Histologically confirmed lesion recurrence, sustained lesion complete response rate (time-to-event analysis), and investigator assessment of cosmetic outcome, 5 years after the last treatment. RESULTS: At 5 years, recurrence was documented in 7 (14%) of 49 lesions (95% confidence interval [CI], 6%-27%) treated with methyl aminolevulinate PDT vs 2 (4%) of 52 lesions (95% CI, 1%-13%) treated with excision surgery (P = .09). Estimated sustained lesion complete response rates were 76% (95% CI, 59%-87%) and 96% (95% CI, 84%-99%), respectively (P = .01). More patients treated with methyl aminolevulinate PDT than surgery had an excellent or good cosmetic outcome: 27 (87%) of 31 patients (95% CI, 70%-96%) vs 19 (54%) of 35 patients (95% CI, 37%-71%) (P = .007). CONCLUSIONS: Long-term follow-up indicates superior efficacy of surgery to methyl aminolevulinate PDT in nodular basal cell carcinoma. However, methyl aminolevulinate PDT is also an effective treatment for this indication and exhibits a more favorable cosmetic outcome.     

Topical 5-aminolevulinic acid mediated photodynamic therapy of superficial basal cell carcinoma using two light fractions with a two-hour interval: long-term follow-up

Photodynamic therapy (PDT) of superficial basal cell carcinoma using topical 5-aminolaevulinic acid (ALA) and 75-100 J/cm2 light dose yields unsatisfactory long-term results. In several animal models, illumination with two light fractions approximately 2 h apart was considerably more effective than single illumination, suggesting the need for a pilot clinical study. Fifteen patients with a total of 86 primary superficial basal cell carcinomas, received topical ALA and were illuminated 4 and 6 h later, both with 45 J/cm2 laser light (633+/-1 nm). Fluorescence spectra were measured before and immediately after each illumination. At a mean follow-up of 59 months (range 44-82), 67 lesions could be evaluated, 56 of which showed a complete response (84%). Cosmesis was good/excellent in 88% of the complete response group and fair in 12%. There was no correlation between protoporphyrin fluorescence and response, but a significant correlation between the percentage of fluorescence left after photobleaching by the first illumination and the amount of protoporphyrin re-synthesized 2 h later. In conclusion, the long-term complete remission rate of fractionated ALA-mediated PDT of superficial basal cell carcinoma as reported here is significantly better than after PDT with single illumination previously reported by others, but equal to studies using single illumination with a much higher light fluence. Further improvement may be possible by reducing the fluence of the first fraction, with constant total fluence.     

Efficacy of photodynamic therapy with methyl aminolevulinate in the treatment of superficial and nodular basal cell carcinoma: an open-label trial

Photodynamic therapy with methyl aminolevulinate (MAL-PDT) is a non-invasive therapy for superficial and nodular basal cell carcinoma (BCC). We performed an open-label trial to evaluate efficacy, safety, tolerability and cosmetic outcome of MAL-PDT in selected patients with superficial and nodular BCCs. Ninety-four superficial and 24 nodular BCCs in 69 patients were treated with 2 to 8 MAL-PDT sessions. Efficacy, safety, tolerability and cosmetic outcome were evaluated at months 1, 3, 6 and 12 after the last MAL-PDT treatment and then every 3 months. One patient discontinued the study for reasons unrelated to study procedures. Complete clinical regression was detected in 84/94 (89.4%) superficial BCCs, and 12/23 (52.2%) nodular BCCs one month after 2 MAL-PDT sessions. No further clinical improvement was observed in either superficial or nodular BCCs with treatment continuation up to a maximum of 8 MAL-PDT sessions. Adverse effects were limited to mild local skin reactions, and cosmetic outcome was rated as excellent or good. Recurrence was observed in 2/84 (2.4%) successfully treated superficial BCCs at 6 and 12 months after treatment discontinuation. Based on the efficacy, tolerability, cosmetic outcome and recurrence rate, our results support the use of MAL-PDT for treatment of superficial BCC and for selected cases of nodular BCC.     

Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial

OBJECTIVE: To compare the efficacy, tolerability, and cosmetic outcome of photodynamic therapy (PDT) using topical methyl aminolevulinate with cryotherapy or topical fluorouracil for treatment of squamous cell carcinoma in situ. DESIGN: Randomized, placebo-controlled study, with follow-up at 3 and 12 months after last treatment. SETTING: Forty outpatient dermatology centers in 11 European countries. PATIENTS: Random sample of 225 patients with histologically confirmed squamous cell carcinoma in situ (lesion size, 6-40 mm) and no evidence of progression. INTERVENTIONS: Treatment with PDT with methyl aminolevulinate (160 mg/g; n = 96) or matching placebo cream (n = 17), cryotherapy (n = 82), or topical fluorouracil (5% cream; n = 30). Methyl aminolevulinate or placebo cream was applied for 3 hours before illumination with broadband red light (75 J/cm2, 570-670 nm). Treatment was repeated 1 week later. Cryotherapy was performed with liquid nitrogen spray. Fluorouracil was applied for 4 weeks. Lesions with a partial response at 3 months were re-treated. MAIN OUTCOME MEASURES: Clinically verified complete response of lesions; blinded and on-site assessment of cosmetic outcome (4-point rating scale). RESULTS: At 12 months, the estimated sustained lesion complete response rate with methyl aminolevulinate PDT was superior to that with cryotherapy (80% vs 67%; odds ratio, 1.77; 95% confidence interval, 1.01-3.12; P = .047), and better than that with fluorouracil (80% vs 69%; odds ratio, 1.64; 95% confidence interval, 0.78-3.45; P = .19). Cosmetic outcome at 3 months was good or excellent in 94% of patients treated with methyl aminolevulinate PDT vs 66% with cryotherapy and 76% with fluorouracil, and was maintained at 12 months.CONCLUSION: Methyl aminolevulinate PDT is an effective treatment option for squamous cell carcinoma in situ, with excellent cosmesis.     

Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial

BACKGROUND: Photodynamic therapy (PDT) is increasingly used as a noninvasive treatment for nodular basal cell carcinoma (BCC), without a sound evidence base. OBJECTIVE: To compare topical PDT, with the use of the sensitizer methyl aminolevulinate, and standard excision surgery in nodular BCC. DESIGN: Prospective, randomized study. SETTING: University dermatology departments. PATIENTS: A total of 101 adults with previously untreated nodular BCC. INTERVENTIONS: Patients received methyl aminolevulinate PDT (n = 52) or surgery (n = 49). The PDT was given twice, 7 days apart, with methyl aminolevulinate cream (160 mg/g) and 75 J/cm(2) red light (570-670 nm). Thirteen patients with a noncomplete response to PDT at 3 months (24% lesions) were retreated. OUTCOME MEASURES: Primary end point was clinically assessed lesion clearance at 3 months after treatment. Secondary end points were sustained response rate at 12 months and cosmetic outcome at 3 and 12 months. Cosmesis and lesion recurrence were further assessed at 24 months. RESULTS: Data from 97 patients (105 lesions) were included in the 3-month per-protocol analysis. Complete response rates did not differ significantly between groups (51/52 [98%] lesions with surgery vs 48/53 [91%] lesions with methyl aminolevulinate PDT; difference [95% confidence interval], 4.8% (-3.4% to 13.0%]; P =.25). At 12 months, tumor-free rates were 50 (96%) of 52 lesions with surgery vs 44 (83%) of 53 with methyl aminolevulinate PDT (P =.15). More patients treated with methyl aminolevulinate PDT than surgery had an excellent or good cosmetic outcome at all time points (significant at 12 and 24 months on patient assessment, P<.05, and at 3, 12, and 24 months on investigator evaluation, P<.001). At 24 months, 5 lesions that had initially cleared with methyl aminolevulinate PDT had recurred, compared with 1 after surgery. CONCLUSIONS: Methyl aminolevulinate PDT is an effective treatment for nodular BCC, and while there is a trend for higher recurrence with this modality, it conveys the advantage over surgery of better cosmesis.     

Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a blinded, randomized, controlled trial

Background  Inflammatory acne vulgaris is a very common condition, particularly in adolescents and young adults, and new effective and well-tolerated treatments are needed.
Objectives  To evaluate the efficacy and tolerability of methyl aminolaevulinate-based photodynamic therapy (MAL-PDT) in patients with moderate to severe facial acne vulgaris in a randomized, controlled and investigator-blinded trial.
Methods  Twenty-one patients were assigned to the treatment group and 15 patients to the control group. The treatment group received two MAL-PDT treatments, 2 weeks apart. Both groups were evaluated 4, 8 and 12 weeks after treatment. Efficacy evaluation included changes from baseline in numbers of noninflammatory and inflammatory lesions, changes from baseline in global acne severity grade and clinical assessments of clinical improvement by patient and evaluating dermatologist. Pain scores during treatment and local adverse effects were also evaluated.
Results  Twelve weeks after treatment the treatment group showed a 68% reduction from baseline in inflammatory lesions vs. no change in the control group ( P =  0·0023). We found no reduction in number of noninflammatory lesions after treatment. All patients experienced moderate to severe pain during treatment and developed severe erythema, pustular eruptions and epithelial exfoliation. Seven patients did not receive the second treatment due to adverse effects.
Conclusions  MAL-PDT proved to be an efficient treatment for inflammatory acne. The treatment was associated with severe pain during treatment and severe adverse effects after treatments. Efforts must be made to optimize the treatment regimen and to avoid adverse effects.     

A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients

BACKGROUND: Transplant recipients have an increased propensity to develop multiple actinic keratoses, which demonstrate an increased transformation rate into invasive squamous cell carcinoma. OBJECTIVE: To evaluate the efficacy and tolerability of topical photodynamic therapy with the new highly tumour-selective photosensitizer methyl aminolaevulinate vs. placebo in the treatment of actinic keratoses in transplant recipients. METHODS: Seventeen transplant recipients with a total number of 129 mild to moderate actinic keratoses were enrolled in a prospective, randomized, double-blind, placebo-controlled study. Two lesional areas within a patient were randomized for two consecutive treatments of topical photodynamic therapy 1 week apart using either methyl aminolaevulinate or placebo cream. Sites were illuminated with 75 J cm(-2) of visible light delivered at 80 mW cm(-2) by a noncoherent light source. Complete resolution and reduction in the number or size of actinic keratoses within the lesional area relative to the initial findings were evaluated at weeks 4, 8 and 16 after treatment. RESULTS: The lesional areas treated with methyl aminolaevulinate were clinically cleared in 13 of 17 patients at 16 weeks. A partial response was recorded in a further three. No reduction in the size or number of actinic keratoses was observed in one area treated with methyl aminolaevulinate and in all placebo-treated areas. Adverse events, such as erythema, oedema and crust formation, were mild to moderate, and treatment was well tolerated by all patients. CONCLUSION: Photodynamic therapy using methyl aminolaevulinate is a safe and effective treatment for actinic keratoses in transplant recipients. It may also reduce the risk of transformation of actinic keratoses to invasive, potentially fatal, squamous cell carcinoma.     

Reflectance confocal microscopy allows in vivo real‐time noninvasive assessment of the outcome of methyl aminolaevulinate photodynamic therapy of basal cell carcinoma

Background Photodynamic therapy (PDT) with methyl aminolaevulinate (MAL) is an approved noninvasive treatment option for basal cell carcinoma (BCC). In vivo reflectance confocal microscopy (RCM) is a noninvasive imaging technique that has proved useful for in vivo real‐time cytomorphological analysis of BCC cells infiltrating the epidermis. Objectives To investigate the use of in vivo RCM to assess the persistence of BCC cells surviving MAL‐PDT. Methods In vivo RCM images of 20 biopsy‐proven BCCs were taken before patients underwent a treatment cycle with MAL‐PDT. Follow‐up after 3 months was performed using clinical examination, RCM and conventional dermoscopy. Treated areas also underwent a targeted 3‐mm punch biopsy for standard haematoxylin and eosin histology stain to establish the clinical and instrumental correlation of the treatment outcome. Results Three months after PDT, clinical examination established that two out of 20 BCCs were persistent; dermoscopy found three out of 20 residual BCCs, but RCM showed that one of these lesions was a false positive, and showed persistent BCC foci in five out of 20 lesions. Histological analysis of targeted biopsies confirmed these results. Conclusions RCM provided noninvasive, early detection of incipient recurrences of BCC after MAL‐PDT. RCM findings steered targeted biopsies and surgical removal, or a new MAL‐PDT, of these subclinical recurrences with minimal invasiveness.     

Repeated 5-aminolevulinic acid-based photodynamic therapy following electro-curettage for pigmented basal cell carcinoma

5-Aminolevulinic acid-based photodynamic therapy (ALA-PDT) in the standard manner is ineffective for pigmented basal cell carcinoma (pBCC), because melanin absorbs the photoactivating light interred for protoporphyrin IX. The objective of this study was to assess the therapeutic outcome of pBCCs with repeated ALA-PDT following removal of pigmentation with electro-curettage. After electro-curettage, 16 pBCCs were treated with a combination of topical application of 20% ALA in O/W emulsion and topical instillation of 10% ALA solution, followed by photoactivating light. ALA-PDT was performed more than three times. Fourteen of 16 pBCCs showed CR. Two pBCCs showing PR or NR were excised. Repeated ALA-PDT following electro-curettage was effective for pBCC.