Photodynamic Therapy for the Treatment of Cutaneous Neoplasia, Inflammatory Disorders, and Photoaging

Authors


Address correspondence and reprint requests to: David J. Kouba, MD, PhD, Henry Ford Health System Dermatology, 3031 West Grand Blvd, Suite 800, Detroit, MI 48202, or e-mail: dkouba1@hfhs.org

Abstract

BACKGROUND Photodynamic therapy (PDT) has demonstrated high efficacy, minimal side effects, and improved cosmetic outcome when used for the treatment of actinic keratoses (AK), basal cell carcinoma (BCC), squamous cell carcinoma, and photoaging.

METHODS To review the literature on the use of PDT in dermatologic surgery using MEDLINE.

RESULTS Published clinical studies using PDT in the treatment of AKs yield overall efficacy rates ranging from 50% to 71% with one treatment to as high as 88% to 90% with two or more treatments. For superficial BCC, initial clearance rates were 76% to 97%, and for Bowen's disease, initial clearance rates ranged from 72% to 94% overall. The use of PDT for photorejuvenation is a relatively new application of this technology, which has shown promise in improving the appearance of fine lines, pigmentary variation, and telangiectasias.

CONCLUSIONS The advantages of photodynamic therapy include the capacity for noninvasive targeted therapy through topical application of aminolevulinic acid and methyl aminolevulinic acid, with outstanding cosmetic results. Although the theory behind the use of chemical photosensitizers and ultraviolet light to treat a wide variety of skin disorders is straightforward, the practical application of this technology is evolving. Additional research into the precise mechanisms of action for specific photosensitizers and optimal light sources will be highly beneficial to the advancement of this technology.

Background

Photodynamic therapy (PDT) involves the selective destruction of targeted abnormal premalignant or malignant cells with the simultaneous preservation of surrounding normal structures.1 The first drugs used for PDT were topically applied dyes, such as eosin red or erythrosine. George Dreyer and Albert Jesionek first used these photosensitizers in the early 1900s in various skin disorders ranging from pityriasis versicolor, psoriasis, and molluscum contagiosum to superficial skin cancers.1 Thomas Dougherty, who first used hematoporphyrin derivative (HPD) in the treatment of primary skin cancer and cutaneous metastases, revisited these experiments in the 1970s.1 The difficulty in using HPD is that, as a systemically administered treatment, increased photosensitization of the skin lasts for several weeks.1 Topical application of HPD was not possible given the large molecular size of the tetrapyrrole rings.1 In 1990, Kennedy and colleagues1 introduced porphyrin precursors, which can easily penetrate the epidermis and result in local photosensitization lasting for only 48 to 72 hours.

Process of Photosensitization and Selective Tissue Destruction

The photosensitizer primarily used in dermatology, 5-aminolevulinic acid (5-ALA), preferentially results in a significantly higher rate of porphyrin induction in malignant or premalignant skin cells than in normal surrounding tissue.2 The reason for the preferential accumulation of photodynamically active porphyrins in malignant and premalignant tissue than in surrounding normal tissue may be various mechanisms such as differences in cellular uptake (variously expressed transmembrane transporters), activities of the heme and porphyrin synthetic pathways, iron bioavailability, properties of the stratum corneum. and variable tissue penetration and distribution.

5-ALA itself is not a photosensitizer but, when applied, is a precursor of the intrinsic intracellular heme biosynthetic pathway, which results in the production of photoactive porphyrins.3 When applied topically, 5-ALA, through a series of enzymatic conversions in the mitochondria and the cytosol, is ultimately converted into protoporphyrin4 Protoporphyrin IX, through its extensive network of alternating double bonds, is essential for the transfer of singlet oxygen species and the generation of free radicals. Although PDT results in singlet oxygen species and free radical formation, these species are relatively short lived, with a radius of only 0.01 μm, and thus have low mutagenic potential for nonlocalized DNA damage.4

The methyl derivative of 5-ALA, methyl aminolevulinic acid (MAL), has also been extensively studied and has been found to have a more selective accumulation of porphyrin in premalignant and malignant skin cells.4–8

Light Sources

Light sources resulting in excitation of photosensitizers include conventional, noncolumated light sources, as well as lasers.9 Conventional light sources are divided into four distinct categories: incandescent lamps, high-pressure arc lamps, low-pressure arc lamps, and light diodes.4,6–12 Incandescent lamps are conventional light bulbs with a range from 400 nm to infrared.4,6–12 Arc lamps contain a gas that conducts electricity at high temperatures. High-pressure arc lamps contain mercury or xenon, and low-pressure arc lamps contain fluorescent material, which is the medium used in traditional room lighting.4,6–12 Light diodes are small semiconductors with a narrow wavelength band of 20 to 50 nm, with no respective infrared emission.4,6–12 The disadvantage of light diodes is the difficulty in focusing the light on the target tissue because they produce a diffuse array of light.4,6–12

Lasers, in contrast to conventional light sources, are monochromatic, columated light sources.4,6–12 Diode lasers (632 and 670 nm) and pulsed dye lasers (585–595 nm) have been used in PDT because their wavelengths match absorption peaks of protoporphyrin IX.4,6–12 Because lasers emit monochromatic and coherent light, they can be focused on even small target areas with sharp boundaries and great precision.4,6–12

Applications of PDT The use of ALA in PDT is currently approved by the Food and Drug Administration (FDA) only for the treatment of actinic keratoses (AKs).12 The off-label use of ALA-PDT to treat nonmelanoma skin cancers, acne, photodamaged skin, and many other dermatological and medical diseases has been investigated. Other dermatological applications include human papilloma virus–associated cutaneous pathologies, lymphocytoma cutis, leishmaniasis, alopecia areata, erythroplasia of Queyrat, benign familial pemphigus, and hidradenitis suppurativa.

Advantages of PDT In addition to preventing the development of scars and dyspigmentation that occurs with surgery, PDT has the added benefit of photorejuvenation and has been used as a treatment to soften the appearance of acne scars, fine lines, and wrinkles.13–16 The mechanism of improvement in the signs of photoaging may be related to the increase in type I collagen production seen in intense pulse light (IPL)-induced activation of ALA and MAL.17 Other possible mechanisms for PDT-induced photorejuvenation are purely speculative and include activation of specific molecular pathways by photosensitizers and a nonspecific immune response.18

Actinic Keratoses

AKs are the most common premalignant condition, with an estimated incidence of 60% in patients aged 40 and older.19 Recently, a number of investigations have demonstrated safety and efficacy, as well as superior cosmetic outcomes, of ALA/MAL-PDT to treat AKs and actinic cheilitis.13–18,20–22 Depending on the photosensitizer used, number and area of treatments, and type of illuminator, complete response (CR) rates vary from 50% to 90%.20–41

Studies Evaluating Efficacy of PDT for Treatment for AKs Recently, the FDA has approved the use of 20% 5-ALA (Levulan Kerastick DUSA Pharmaceuticals Inc., Wilmington, MA) before illumination with blue light24,42 (Table 1). Levulan is approved for use in combination with blue light (417 nm) after the pivotal phase II/phase III series by Jeffes and colleagues.21,22,24 In the phase II study, 39 patients with hyperkeratotic AKs of the face and scalp were treated after 14 to 18 hours of preincubation with 5-ALA with 16 minutes and 40 seconds of blue light. With these prolonged incubation times, pain was common during treatment, and extensive post-treatment erythema and edema were observed. At 8 weeks after the first treatment, 66% of AKs had resolved. For AKs that persisted, a second treatment was given, and at 16 weeks, 85% clearance was observed.

Table 1. Photodynamic Therapy (PDT) for Actinic Keratoses (AKs)
AuthorLocationDosage RegimenResults
  1. ALA=aminolevulinic acid; MAL=methyl aminolevulinic acid; IPL=intense pulsed light.

Jeffes et al.21Face and scalpALA-PDT with blue light at 10 J/cm288% clearance with ALA+blue light vs 6% vehicle+blue light
Szeimeis et al.31Head and neck, lower extremitiesMAL-PDT with Waldmann PDT 1,200, 160 mW at 150 J/cm2At 3 months, 71% complete remission of head lesions, only partial remission of extremity lesions
Alexiades-Armenakas26Face and scalpALA-PDT with V-beam laser (Candela Corporation), 4–17.5 J/cm2, pulse width 1.5–40 ms, 7-mm spot size, and cryogen spraying at 20 ms delay and 30 ms durationComplete clearance of head lesions
Calzavara-Pinton et al.32Face and scalpALA-PDTInitial follow-up at 3–6 months, no clinical recurrence, at 24–36 months, 10% clinical recurrence
Fritsch et al.28 Pariser et al.26 Lubritz et al.35Face and scalpMAL-PDT with Curelight incoherent light source (570–670 nm, 100–200 mW/cm2)Complete clearance: 1 treatment, 68%; 2 treatments, 90%
Kurwa et al.36Bilateral handsMAL-PDT with incoherent light source (1,200 W metal halogen lamp; 580–740 nm)5-ALA: 73% reduction in AKs
Piacquadio et al.24Face and scalpALA-PDT with blue light set at 417 ± 5 nmResponse rate at Week 12 89% (133/149 lesions responded) for ALA and 13% (7/52) for placebo
Touma et al.25Face and scalpALA-PDT with pre-application to the entire area for 1, 2, or 3 hours. Lidocaine hydrochloride (3%) or vehicle cream was also applied to the entire area 45 minutes before exposure to 10 J/cm2 of blue light.At 1 and 5 months post-treatment, there was significant reduction in AKs in all groups. Different delta-ALA application times and pretreatment with urea cream or lidocaine had no significant effect on efficacy.
Fritsch et al.33Face and scalpALA-PDT with green light versus red light for AKsGreen and red light equally effective in AK clearance. Green light significantly less painful than red light
Kim et al.37Face and scalpALA-PDT, single treatment using IPLIPL for PDT: clinical clearance, 50%; histological clearance, 42%
Tschen et al.38Face and scalpALA-PDT with blue light set at 417 ± 4 nmAt 2-month follow-up, 72% of lesions were completely resolved. Second treatment given at 2 months. At 4 months of follow-up, 86% resolution rate. At 1-year follow-up, 78% (537/688) remained resolved.
Redbord et al.39Face and scalpALA-PDT with blue light90% of patients had significant AK improvement or clearance
Zane et al.40FaceMAL-PDT with red light (37 J/cm2) with 2 treatments at monthly intervals.88.3% clearance after 2 treatments at monthly intervals. High-resolution echocardiography showed increase in skin thickness and pixel count and reduction of subepidermal low-echogenic band thickness.
Gold et al.27FaceALA-PDT with blue light83% of AKs responded, also noted improvement in skin signs of photoaging (see Photorejuvenation section)
Goldman et al.45FaceALA-PDT blue light90% of AKs responded, also noted improvement in skin signs of photoaging (see Photorejuvenation section)
Avram et al.46FaceALA-PDT with IPL69% AK response, also noted improvement in skin signs of photoaging (see Photorejuvenation section)

In the subsequent phase III trials by Piacquadio and colleagues,24 the same conditions of 14 to 18 hours of pre-incubation with 5-ALA with 16 minutes and 40 seconds of blue light were used on 243 patients with nonhyperkeratotic AKs. A complete clearance rate of greater than 70% was achieved at 12 weeks. A second treatment was given at 12 weeks for nonresponding lesions, and at 24 weeks, a complete clearance rate of 88% was achieved. A secondary end point, cosmetic outcome, was evaluated, with 94% of patients reporting their cosmetic outcome as good or excellent.

It was noted in the phase II/III clinical trials for ALA-PDT that there was significant improvement in signs of photoaging after treatment.21,22,24 A number of authors found similar improvements in the skin signs of photoaging after ALA-PDT treatment for AKs.13–18

Several subsequent trials demonstrated that similar efficacy could be obtained with shorter incubation times, with benefits of convenience and less pain, erythema, and edema. Touma and colleagues25 were the first to demonstrate that shorter incubation times (1 hour) were as efficacious as longer incubation times. Alexiades-Armenakas and colleagues26 reported on ALA-PDT with PDL as the light source, with preincubation time of 3 hours. Gold and colleagues reported results of ALA-PDT with blue light, with a preincubation time of 1 hour with marked success, with 90% of AKs clearing after one treatment.27

Although blue light was officially used in these studies, which led to FDA approval of 5-ALA-PDT for AKs,28–30 red wavelengths have been the most highly reported. In addition, Fritsch and colleagues28 also reported that green light is as effective as red light in the treatment of AKs and is significantly less painful. IPL has consistently been the most efficacious light source at improving skin signs of photoaging.13–23,43

Comparison Studies for AK Treatments

ALA-PDT Versus Cryotherapy When the results of three of the largest clinical trials comparing MAL with placebo-PDT and cryotherapy were pooled from Lang and colleagues,41 (Table 2) Lubritz and colleagues,35 and Pariser and colleagues,34 it was found that the overall response to MAL-PDT was 68% after one treatment and 90% after a second treatment performed 1 week later, compared with a clearance rate of 71% with cryotherapy and 35% with placebo-PDT, although adverse side effects after cryotherapy were significantly more prevalent, with 29% of lesions having some degree of hypopigmentation after cryotherapy, versus only 6% of lesions treated with PDT.

Table 2. Comparison Studies of Treatments for Actinic Keratoses (AKs)
AuthorLocationDosage RegimenResults
  1. PDT=photodynamic therapy; ALA=aminolevulinic acid; MAL=methyl aminolevulinic acid; FU=fluorouracil; IPL=intense pulsed light.

Szeimies RM et al.31Scalp, face, and extremitiesMAL-PDT with MAL applied 3 hours before broad-spectrum red light (75 J/cm2) vs single treatment with cryotherapyOverall efficacy MAL, 69%; cryotherapy, 75%. Scalp had best overall response: MAL, 80%; cryotherapy, 82%. Cosmetic outcome: MAL, 96%; cryotherapy, 81%.
Lang et al.41 Lubritz et al.35 Pariser et al.34Face and scalpMAL-PDT vs cryotherapy, 2 treatments given 1 week apartMAL-PDT: 68% (one treatment) and 90% (two treatments) 1 week later. Cryotherapy, 71%; placebo-PDT, 35%; hypopigmentation: 29% cryotherapy, 6% PDT
Kasche et al.30Face and scalpMAL-PDT with red light (Waldmann PDT 1,200) with a light dose of 100 J/cm2 delivered at a dose rate of 160 mW/cm2MAL: 19% of patients discontinued treatment secondary to pain. ALA: 54% of patients discontinued treatment secondary to pain.
Kurwa et al.29Bilateral hands5-AL- PDT given in a single treatment with irradiation using an incoherent light source (1,200 W metal halogen lamp; 580–740 nm)5-ALA (single treatment): 73% reduction in AKs. 5-FU (two times a day × 2 weeks): 71% reduction in AKs
Gold et al.16FaceIPL-ALA-PDT vs IPL alone: for skin type I-III wavelength <550 nm, for skin type IV: wavelength ≥570 nmIPL-ALA-PDT: AKs resolved at a rate of 78%. IPL alone: AKs resolved at a rate of 54%.

In a European multicenter randomized prospective study by Szeimes and colleagues,31 MAL-PDT was compared with cryotherapy in the treatment of AKs. Patients received a single treatment with MAL-PDT and broad-spectrum red light (75 J/cm2) or a double freeze–thaw cycle of liquid nitrogen cryotherapy. The efficacy of MAL-PDT single application at 3 months was 69%, versus 75% for cryotherapy. Cosmetic outcome was better for MAL-PDT: 96% for MAL-PDT, versus 81% for liquid nitrogen.

ALA-PDT Versus 5-Fluorouracil Cream Kurwa and colleagues29 compared the effects of 5-ALA-PDT with topical 5-fluorouracil (FU) in 17 patients with AKs of both hands. There was a 73% reduction in lesional areas affected with AKs on both hands after a single treatment of 5-ALA-PDT, which was similar to the 71% reduction of lesional area using 5-FU twice daily for 2 weeks.

MAL as Photosensitizer Studies using MAL have also shown excellent preferential accumulation of porphyrin photosensitizers and AK lesion clearance. In 2003, Pariser and colleagues34 published the results of a randomized double-blind study comparing MAL with placebo cream in the treatment of AKs. Complete lesion response at 3 months was 89% with MAL-PDT, versus 38% with placebo (p=.001).

MAL has been reported to be preferable to ALA in terms of patient comfort. Kasche and colleagues30 reported the results of a study in which a significantly greater proportion of patients experienced more pain and discontinued therapy secondary to pain with ALA than with MAL under the same red light source at the same fluence. Only 14% of the patients treated with MAL discontinued treatment before reaching the required light dose of 100 J/cm2, versus 54% of patients treated with ALA.

Summary of AK Treatment with PDT Overall clearance rates for the treatment of AKs with PDT ranged from 50% to 71% when one treatment was performed and up to 88% to 90% when two or more treatments were performed.28–41,44–46 The face and scalp had higher clearance rates than other anatomic sites, particularly extremity lesions, which demonstrated only partial remission. In addition, PDT was noted to result in significant improvement in background photoaging and actinic damage, which provides significant advantages over other standard treatment approaches for AKs.

Basal Cell Carcinoma

Topical PDT has also demonstrated efficacy in the treatment of basal cell carcinoma (BCC). Clearance rates for BCC using 5-ALA and MAL-PDT range from 76% to 97% for superficial tumors to 64% to 92% for nodular BCC (with one study with a small sample size of 6 patients failing to demonstrate clearance of nodular BCC).47–62

Superficial BCC In 2001, Morton and colleagues63 provided one of the first reports of the success of ALA-PDT (Table 3) (n=40) in a number of patients with large superficial BCCs; there was an initial rate of clearance of 88% after one to three treatments, with four recurrences, proven according to histology, within 34 months (range 12–60 months).

Table 3. Treatment of Superficial Basal Cell Carcinoma (BCC) with Photodynamic Therapy (PDT)
AuthorLocationDosage RegimenResults
  1. ALA=aminolevulinic acid; MAL=methyl aminolevulinic acid; DMSO=dimethylsulfoxide.

Morton et al.63Face, scalp, trunk, and extremitiesALA-PDT for 1–3 treatments.
Three patients with nevoid BCC syndrome (Gorlin's syndrome) treated until clearance achieved and followed for 12–52 months
Superficial BCCs (n=40), 88% initial clearance with 1–3 treatments, 10% (4/40) recurrence within 34 months nevoid BCC syndrome: 3 patients: cleared 90% (52/58) tumors, with 2 recurrences during 41 months
Haller et al.64Face, scalp, trunk, and extremitiesALA-PDT, 1 treatment with median follow-up of 27 monthsAll initially cleared, 4% relapse rate (1/26) over 27 months
Soler et al.65Face, scalp, trunk, and extremitiesALA-PDT 15 minutes of local pretreatment with 99% DMSO before topical application of 20% ALA with DMSO (2%) and ethylenediaminetetraacetic acid (2%) for 3 hours before light exposure with either laser (red light, 630 nm) or a broadband lamp (570–740 nm)83 patients with 245 superficial BCC, At 6 months, complete response: 86% (n=95) in the red light group, 82% (n=110) in the broadband lamp group. Cosmetic results, 84% in the red light group had a good or excellent cosmetic result, 92% (n=101) in the broadband lamp group had excellent or good cosmetic results.
Kennedy et al.4Face, scalp, trunk, and extremitiesALA-PDT, 1 treatment for superficial BCC (no lesion preparation specified)At 2–3 months of follow-up, 90% (72/80) had responded completely, 7.5% (6/80) had partially responded, and 2.5% (2/80) had not responded.
Svanberg et al.47Face, scalp, trunk, and extremitiesALA-PDT 1 treatment using laser light (630 nm) (no lesion preparation specified)3-week complete response: 90%
Fijan et al.48Face, scalp, trunk, and extremitiesALA-PDT 1 treatment for superficial BCC (no lesion preparation specified)20 months after 1 treatment session, 88% (30/34) of the superficial BCCs were resolved.
Calzavara-Pinton51Face, scalp, trunk, and extremities1 treatment with ALA-PDT (no lesion preparation specified)At 24–36 months, 87% (20/23) of superficial BCCs were resolved.
Fink-Puches et al.49Face, scalp, trunk, and extremitiesALA-PDT for superficial BCCs, 1 treatment (no lesion preparation specified)85% (82/95) responded completely initially. The follow-up ranged from 3–60 months (median 19 months), after which 66% (45/81) remained in remission
Baptista et al.50Face, scalp, trunk, and extremitiesALA-PDT for superficial BCCs with treatment until clearance achieved76% (49/64) cleared completely with an average of 4 sessions
De Haas66Face, scalp, trunk, and extremitiesALA-PDT with fractionated light of 20 J/cm2 was used 4 hours after ALA application and 80 J/cm2 was used 6 hours after application, with a period of darkness between, versus continuous light at 75 J/cm2 4 hours after ALA applicationAt 1 year of follow-up, fractionated light gave a significantly better clearance rate (97%; 252/262) than continuous light (89%; 211/243)
Wennberg et al.74Face, scalp, trunk, and extremities1 × ALA-PDT (no lesion preparation performed)6 month lesion complete response: 92%–49% had no “cosmetic side effects: and 42% showed “some adverse cosmetic side effects”
Wang et al.52Face, scalp, and extremities1 × ALA-PDT vs 2 × cryotherapy, retreated after 3 months when necessary (pretreatment with scalpel blade lesion preparation)12-month recurrence rate 38% for ALA-PDT, vs 7% for cryotherapy.
Basset-Seguin et al.53,54Face, scalp, trunk, and extremities1 × MAL-PDT vs 2 × cryotherapy. When necessary, after 3 months, retreatment with 2 treatments of MAL-PDT or cryotherapy was given (2 treatments 7 days apart) (lesion preparation performed before PDT and cryotherapy)3 month lesion complete response: MAL-PDT 97% vs cryotherapy 95%
Nikkels et al.55Face, scalp, trunk, and extremitiesALA-PDT vs 3 monthly courses of imiquimod (each consisting of 3 weekly applications for 3 weeks followed by one week off treatment)Clinicohistological cure at 1 month: 12/13 PDT, 6/8 imiquimod, 3/13 PDT cases had minimal pain during illumination and crust formation. Variable erythema, oozing, ulceration, and crusting were observed in all imiquimod-treated lesions.
Rhodes et al.57Face, scalp, trunk, and extremitiesMAL-PDT (two doses given 7 days apart) versus surgical excision;
light source: 75 J/cm2 red light (570–670 nm)
At 3 months, tumor-free rates: 98% (n=51/52) with surgery, 91% (n=48/53) with MAL-PDT. At 12 months, tumor-free rates: 96% (50/52) with surgery, 83% (44/53) with MAL-PDT. At 24 months, tumor-free rates: 94% (49/52) with surgery, 74% (39/53) with MAL-PDT. More patients treated with MAL-PDT than surgery had an excellent or good cosmetic outcome

Haller and colleagues found better success in terms of initial clearance and long-term relapse (evaluated clinically and histologically) with a series of two treatments with ALA-PDT.64 Twenty-six lesions were treated twice with ALA-PDT, with an interval of 7 days between the two treatment sessions. They observed a CR rate of 100% 1 month after treatment. Only one lesion relapsed (16 months post-PDT, recurrence proven on histology), a relapse rate of 4%.

Many studies identified better success for PDT treatment of BCCs with prior lesion preparation using a variety of modalities, including pre-application of dimethylsulfoxide (DMSO), debulking curettage, and scalpel debridement. A randomized study performed by Soler and colleagues65 compared the clinical and cosmetic outcome of superficial BCCs pretreated with DMSO using ALA-PDT. Standard treatment involved 15 minutes of local pretreatment with 99% DMSO before topical application of ALA for 3 hours before light exposure with laser or a broadband lamp. At 6 months after treatment, a clinical CR was achieved in 86% of BCCs in the laser group and 82% in the broadband lamp group.

De Haas and colleagues66 compared ALA-PDT using two doses of fractionated light of 20 J/cm2 given 4 hours after ALA application and 80 J/cm2 given 6 hours after application, with a period of darkness in between, with continuous light at 75 J/cm2 given 4 hours after ALA application. At 1-year follow-up, fractionated light gave a higher clinical clearance rate of 97% (252/262) than continuous light of 89% (211/243) (p<.05).

Two studies compared the results of treatment of superficial BCC with PDT with cryotherapy. In the first study by Wang and colleagues,52 the clinical recurrence rates for ALA-PDT were 5%, versus 13% for cryotherapy, but the 12-month histologic recurrence rate for ALA-PDT was 25%, versus 15% for cryotherapy. Thus, in spite of low clinical evidence of recurrence with ALA-PDT, significantly greater histologic recurrence was observed. In contrast, Basset-Seguin and colleagues53,54 found high rates of initial histologic clearance with MAL-PDT (97%) and cryotherapy (95%), with similar recurrence rates (on histology) at 36 and 48 months (recurrence rates of 22% for MAL-PDT and 19% for cryotherapy at 48 months).

Nikkels and colleagues55 compared initial and long-term clinical and histological cure and patient tolerability of MAL-PDT with those of topical imiquimod. Eight patients with superficial BCC were treated with imiquimod using three monthly courses each consisting of daily applications for 3 weeks followed by 1 week off treatment. Biopsies were taken before and after 3 months. Clinical and histologic cure was obtained in 12 of 13 PDT cases as assessed after 1 month and in six of eight imiquimod cases after 3 months. Minimal pain during illumination and crust formation were observed in three of 13 PDT cases. Variable erythema, oozing, ulceration, and crusting were observed in all imiquimod-treated lesions. Long-term clearance rates of imiquimod for the treatment of BCC have consistently been reported to be significantly lower than those of other treatment modalities. In a large retrospective study in the Australian literature, the cure rate for BCC with imiquimod was 90% at 6 months, although the cure rate at 2 years dropped to 70%.56

Rhodes and colleagues57 performed a prospective randomized study to compare the effectiveness of MAL-PDT with red light with the effectiveness of surgical excision regarding tumor clearance and recurrence on histology. Initial response rates did not differ significantly between groups (51/52 (98%) lesions with surgery vs 48/53 (91%) lesions with MAL-PDT), but at 12 months, tumor-free rates were 96% for lesions with surgery, versus 83% for lesions treated with MAL-PDT (p=.05). At 24 months, an additional five lesions that initially cleared with MAL-PDT had recurred, compared with one with surgery.

Nodular BCCs Clearance rates for nodular BCC (Table 4) using 5-ALA-PDT varied more markedly than those for superficial BCC, ranging from 64% to 92% in nodular BCC (with one study with a small sample size of 6 patients failing to demonstrate clearance of nodular BCC58).

Table 4. Treatment of Nodular Basal Cell Carcinoma (BCC) with Aminolevulinic Acid Photodynamic Therapy (ALA-PDT)
AuthorLocationDosage RegimenResults
  1. DMSO=dimethylsulfoxide; MAL=methyl aminolevulinic acid; Er:YAG=erbium-doped yttrium aluminium garnet.

Thissen et al.60Face, scalp, trunk, and extremitiesALA-PDT with debulking curettage before treatment3 months after PDT, 22/24 (92%) of the nodular BCCs showed complete response on clinical and histopathological examination.
Soler et al.61Face, scalp, trunk, and extremitiesALA-PDT with pretreatment with debulking curettage and the application of DMSO, a penetration-enhancing moleculeDemonstrated clearance of 92% of the nodular BCCs (n=119) with the addition of debulking curettage and the application of DMSO.
Soler et al.68Face, scalp, trunk, and extremitiesALA-PDT 350 nodular BCCs. Tumors were curetted before PDT, and MAL was applied to all tumors for 3 hours before light application (broadband halogen light source with light doses from 50–200 J/cm2)The overall cure rate was 79% (310/350); 277/310 (89%) remained in complete response at 4 years, and cosmetic outcome was excellent or good in 98% (n=272).
Svanberg et al.47Face, scalp, trunk, and extremitiesPhotofrin, applied 24–48 hours before 630-nm laser irradiationAfter a 6- to 14-month follow-up, 64% (16/25) of the nodular BCCs resolved with 1 session. All of the nodular BCCs resolved after 2 sessions.
Fijan et al.48Face, scalp, trunk, and extremities1 treatment session with ALA-PDT20 months after 1 treatment session, 32% (7/22) of the nodular BCCs were resolved
Calzavara-Pinton51Face, scalp, trunk, and extremities1 treatment session with ALA-PDTAt 24-36 months, 50% (15/30) of nodular BCCs remained in remission. None of the 4 pigmented BCCs initially responded to the treatment
Baptista et al.50Face, scalp, trunk, and extremities1 treatment with ALA-PDT for nodular BCCsOf 6 nodular BCCs, only 2 responded partially, and none responded completely
Smucler R54Face, scalp, trunk, and extremities1 treatment session with MAL-PDT only, Er:YAG only, Er:YAG+PDTFinal efficacy, 99.0% for Er:YAG+PDT, 94.8% for PDT only, and 91.7% for Er:YAG only. The combined method also provided the best aesthetic results (scale: 1=best to 4=worst) of 1.23 ± 1.23, compared with 1.67 ± 0.76 for PDT only and 1.83 ± 0.95 for Er:YAG laser only.
Tope et al.69Face, scalp, trunk, and extremities2 treatments with MAL-PDT (7 days apart) (lesion preparation performed) vs surgical excision3-month lesion complete response: 91% for MAL-PDT vs 98% for surgery. 60-month lesion recurrence rates: 14% for MAL-PDT and 4% for surgery. Excellent or good cosmetic outcome at 3 months: 82% for MAL-PDT and 33% for surgery.
Foley et al.75Face, scalp, trunk, and extremities2 treatments with MAL-PDT (7 days apart, with retreatment after 3 months when necessary) vs placebo PDT6-month lesion complete response: MAL-PDT, 82% and 79% (clinical and histologic clearance); placebo, 49% and 35% (clinical and histologic clearance). Excellent or good cosmetic outcome in 92% of patients treated with MAL-PDT.
Rhodes et al.57Face, scalp, trunk, and extremities: Small nodular BCCs1 treatment with ALA-PDT (curettage lesion preparation)3-month lesion complete response: 92%. Excellent or good cosmetic outcome in 95% of patients with ALA-PDT.
Wang et al.52Face, scalp, trunk, and extremities1 treatment ALA-PDT vs 2 treatments with cryotherapy, lesions retreated after 3 months when necessary (scalpel blade lesion preparation)12-month recurrence rate: 13% for ALA-PDT, 21% for cryotherapy. Excellent or good cosmetic outcome (total study population superficial BCC+nodular BCC) in 93% of patients treated with ALA-PDT, vs 54% for cryotherapy

The limited penetration of 5-ALA and light into the deeper layers of the epidermis and dermis can in part explain lack of response to deeper tumors, particularly nodular BCC. In support of this hypothesis, Kalka and colleagues59 reported that lesions less than 2 mm thick have a better outcome with PDT than their thicker counterparts.

Thissen and colleagues60 reported higher rates of clearance of nodular BCC than other investigators (22/24 tumors treated) with debulking curettage performed before ALA-PDT. Twenty-two (92%) of the 24 nodular BCCs showed a CR on clinical and histopathological examination. Similarly, Soler and colleagues61 demonstrated clearance of 92% of the nodular BCC (n=119) with the addition of debulking curettage and the application of DMSO, a penetration-enhancing molecule.

To account for limitations in efficacy of nodular BCC relating to difficulty of photosensitizer penetration throughout the depth of the tumor, Thissen and colleagues62 and De Blois and colleagues67 reported that, for thicker skin cancers, higher fluorescence levels and protoporphyrin IX levels after intralesional administration of 5-ALA as opposed to topical application. However, because photodynamic therapy using intralesional 5-ALA in nodular BCC has only been demonstrated only in case reports and small case series, additional large studies are needed to substantiate its efficacy.

To assess long-term cure rate, cosmesis, histologic recurrence rates after ALA-PDT of superficial and nodular BCCs, Soler and colleagues performed the largest study to date on 350 BCCs treated with ALA-PDT.68 Nodular BCCs were curetted before PDT, and ALA was applied to all tumors for 24 hours or 3 hours before illumination from a broadband halogen light source. Of the 350 lesions treated, 310 responded completely (79% CR rate).

Tope and colleagues performed a multicenter randomized open-label study comparing MAL-PDT with surgical excision.69 The 3-month lesion clinical response rate was highly equivalent for both treatments: 91% for MAL-PDT versus 98% for surgery, although at 60 months, the lesion recurrence rates (assessed on histology) were significantly higher for MAL-PDT (14%) than for surgery (4%).

Smucler and colleagues54 performed a recent study on nodular BCCs comparing erbium-doped yttrium aluminium garnet (Er:YAG) laser ablation alone with Er:YAG laser with PDT and demonstrated greater clinical clearance rates and better cosmetic outcomes with the combination therapy of Er:YAG and PDT. Statistically, the combination therapy demonstrated the most effective treatment at all time intervals, with a final clinical efficacy of 99.0%, versus 94.8% for PDT only and 91.7% for Er:YAG laser only.

Given the significant variability reported in initial clearance and recurrence rates of ALA and MAL-PDT for the treatment of nodular BCCs, Mohs surgery or surgical excision with standard margins remains the treatment of choice.

Difficult-to-Treat BCCs BCCs difficult to treat using conventional means include large tumors, recurrent lesions, and lesions located in the mid-face (H-zone) (Table 5). Mohs and standard surgical excision is the primary treatment of choice, given the overall lower and variable efficacy rates of tumors in these higher-risk categories.

Table 5. Difficult-to-Treat Basal Cell Carcinoma (BCC) Treated Using Photodynamic Therapy (PDT)
AuthorLocationDosage RegimenResults
  1. MAL=methyl aminolevulinic acid.

Vinciullo et al.70Difficult-to-treat BCCs, defined as large lesions, lesions in the H-zone, patients at high risk of surgical complicationsMAL-PDT, 3 hours of MAL cream preincubation to red light 75 J/cm2 red light (570–670 nm) (lesion preparation performed)28 lesions: sustained lesion complete response rate: 90% at 3 months, 84% at 12 months, 78% at 24 months. Overall cosmetic outcome was excellent or good in 79% at 12 months and 84% at 24 months
Horn et al.71Difficult-to-treat BCC on recurrent, large, or H-zone lesions2 treatments of MAL-PDT, retreated after 3 months when necessary3-month lesion complete response: 80%. 60-month recurrence rate: 38%. Excellent or good cosmetic result in 94% at 24 months.
Kuijpers et al.72BCCs with a high risk of complications or disfigurement:
52% of lesions were large (>15 mm on the face, >20 mm on extremities, and >30 mm on the trunk), 43% were located on the ears, 13% were recurrent, 15% were in areas of sun-damaged skin on the face.
MAL-PDT: Each lesion was treated twice with 1 week between treatmentsAt 3-month follow-up, complete response in 80% of superficial, 73% of nodular, and 43% of mixed lesions. At 1-year follow-up, recurrence rate of 32% in lesions of the neck and trunk, 0% on the face, scalp, and extremities.

To investigate the efficacy and safety of PDT using MAL for BCCs defined as “difficult to treat” (large lesions, in the H-zone, or in patients at high risk of surgical complications), Vinciullo and colleagues performed a prospective multicenter efficacy study.70 The lesion CR rate (as assessed according to histology) at 3 months was 89% (131/148). At 12 months, 10 lesions recurred, a cumulative treatment failure rate of 18% (27/148). At 24 months, an additional nine lesions recurred, resulting in a cumulative treatment failure rate of 24% (36/148).

Horn and colleagues71 performed a similar open-label multicenter study in Australia, with 80 “high risk” superficial BCCs and 49 “high risk” nodular BCCs treated with MAL-PDT. After lesion preparation, two treatments with MAL-PDT were given initially and, where necessary, repeated at 3 months. The 3-month lesion CR (as assessed according to histology) was 80%, and long-term follow-up at 60 months revealed a recurrence rate of 38%.

Kuijpers and colleagues72 also studied MAL-PDT in a clinical trial for treatment of BCCs with a high risk of complications or those at risk for disfigurement as a result of complicated surgical interventions. In these high-risk BCCs, 52% of lesions were large (>15 mm on the face, >20 mm on the extremities, and >30 mm on the trunk), 43% were located on the ears, 13% were recurrent (recurrence rate of at least twice in 1 year), and 15% were in areas of sun-damaged skin. Each lesion was treated twice, with a 1-week interval between treatments. At 3 months of follow-up, CR was 80% for superficial; 73% for nodular; and 43% for micronodular, infiltrative–morpheaform, and mixed subtypes. At 1-year follow-up, the recurrence rate was 32% in lesions of the neck and trunk and no recurrence in lesions of the face, scalp, and extremities.

Nevoid Basal Cell Carcinoma Syndrome

Morton and colleagues treated a large series of tumors (n=58) with BCC nevus syndrome and demonstrated that PDT cleared 52 of 58 lesions (90%), with a 10% recurrence rate during 41 months (range 12–52 months).63 Similarly, isolated case reports in the literature have documented the efficacy of PDT in patients nevoid basal cell carcinoma syndrome (NBCCS), including in patients as young as 13 and in cosmetically sensitive areas, such as the eyelid.12,63 The tissue-sparing and chemopreventive nature of PDT in patients highly susceptible to BCCs, such as patients with NBCCS and undergoing organ transplant, make it an ideal treatment choice for these patients. Based upon efficacy reported in the literature, in their Guidelines on the Use of Photodynamic Therapy for Nonmelanoma Skin Cancer: an International Consensus, the International Society for Photodynamic Therapy in Dermatology recommends PDT as a treatment for superficial and nodular BCCs in patients with NBCCS.12

Summary of BCC Treatment with PDT PDT has been shown to be effective for BCC, with higher and more consistent clearance rates for superficial BCCs (76–97%) than nodular BCCs (64–92%).48–76 Tumor subtype (superficial tumors having the highest efficacy, nodular having intermediate efficacy, and morpheaform having the lowest efficacy), pretreatment modalities (aggressive surgical and chemical debulking curettage enhances efficacy), anatomic location (high-risk areas for recurrence with surgery on the head and neck also demonstrate high rates of recurrence with PDT), and measure of clearance (clinical clearance data alone underestimates true histologic clearance) can explain the variability in clearance and recurrence rates for BCCs with PDT. These cure rates for PDT compare with rates of 42% to 100% for topical immunomodulators (e.g., Aldara), 80% to 85% for cryotherapy, 90% to 95% for electrodesiccation and curettage, 95% for excision with standard margins (0.3–0.4 cm), and 99% for Mohs micrographic surgery.76–89 The International Society for Photodynamic Therapy recommends PDT as an effective and reliable treatment option only for superficial BCCs.12 Treatment of nodular BCCs should be restricted to specialized cases, such as NBCCS, in which the tissue-sparing and chemopreventive advantages of PDT over surgery are significant.

Bowen's Disease

A number of investigators have described the experimental use of PDT for squamous cell carcinoma (SCC) in situ, or Bowen's disease (Table 6).

Table 6. Treatment of Bowen's Disease Using Photodynamic Therapy (PDT)
AuthorLocationDosage RegimenResults
  1. ALA=aminolevulinic acid; MAL=methyl aminolevulinic acid.

Stables et al.77Face, trunk, and extremitiesALA-PDT: 2 treatmentsAfter 2 treatments, 3 lesions achieved a complete clinical and histological response with good cosmetic results.
Morton et al.78Face, trunk, and extremitiesMAL-PDT for large lesions of Bowen's disease, initial lesion preparation performed and 3 hours of MAL exposure35 (88%) of 40 large patches of Bowen's disease cleared after 1–3 treatments of delta-ALA-PDT; 4 lesions recurred over 12 months.
Morton et al.79Face, trunk, and extremitiesA randomized comparison study of ALA-PDT using red (630 ± 15 nm) or green (540 ± 15 nm) light in the treatment of Bowen's disease.The initial clearance rate for lesions treated using red light was 94% (30/32) vs 72% (21/29) for green light (p=.002). At 12 months, the clearance rates were 88% for red light and 48% for green light.
Svanberg et al.47Face, trunk, and extremitiesALA-PDT with activation using a 630-nm laserAfter 1 treatment, at follow-up of 6–14 months, 90% (9/10) of lesions retained a complete response.
Fijan et al.48Face, trunk, and extremitiesALA-PDT applied for 20 hours under occlusion, then exposure to red-filtered lightAt 20-month follow-up, 100% clearance in 8 patients with 10 lesions.
Britton et al.80Face, trunk, and extremitiesALA-PDT, 5% ALA applied under occlusion for 4 hours, irradiation with Candela pulsed dye laser (585 nm)At 2 months, 8/17 treatment sites could not be assessed because of overlying crusts and erosion. At 1-year follow-up, 82% (14/17) were in complete remission.

Stables and colleagues77 reported one of the initial studies using PDT involving ALA as the photosensitizer for treatment of Bowen's disease. After two treatments, complete clinical and histological response was achieved in three lesions, with good cosmetic results. Subsequently, in 2001, Morton and colleagues78 cited a larger case series of 40 patients with Bowen's disease treated with ALA-PDT; 35 (88%) of 40 large patches of Bowen's disease (diameter >20 mm) cleared after one to three treatments with ALA-PDT, although four patches recurred within 12 months. Morton and colleagues treated 10 patients with multiple (≥3) patches of Bowen's disease, with 44 or 45 (98%) clearing after ALA-PDT, although four recurred over 12 months.82

Morton and colleagues79 subsequently performed a study comparing green light with red light for the treatment of Bowen's disease; red light was found to be less effective than green light. The initial clearance rate for lesions treated using red light was 94%, compared with 72% for those receiving green light (p=.002). Over the following 12 months, there were two recurrences in the red light group and seven in the green light group, reducing the clearance rates to 88% and 48%, respectively.

Britton and colleagues80 reported 17 lesions treated with 5% ALA under occlusion for 4 hours irradiated with a pulsed dye laser (585 nm). At 2 months post-treatment, eight treatment sites could not be assessed because of overlying crusts and superficial erosion. At 1-year follow-up, of the 17 lesions treated, 14 (82%) demonstrated complete clinical response. Troubling in terms of patient tolerability in these studies was the observation that two patients with Bowen's disease requiring more than one treatment refused treatment secondary to discomfort.87

Svanberg and colleagues47 reported treatment of Bowen's disease in three patients with 10 lesions after 6 to 14 months of follow-up, 90% (9/10) of these lesions retained a CR after having received one treatment. Four of these lesions were noted to heal with some hyperpigmentation. Fijan and colleagues48 reported similarly high clearance rates of Bowen's disease with PDT; at 20 months of follow-up, 100% clearance was achieved.

In a number of reports in the literature, the post-treatment morbidity with PDT for Bowen's disease was higher than with other treatment modalities, as well as with PDT for the treatment of other skin conditions. Further studies are needed to evaluate treatment efficacy of PDT in Bowen's disease.

Comparison Treatment Studies of Bowen's Disease Salim and colleagues81 performed a study comparing the efficacy of 5-ALA-PDT for Bowen's disease with that of 5-FU (Table 7). The PDT group was treated with 20% 5-ALA applied 4 hours before illumination with red light. A repeat treatment cycle was performed at 6 weeks for PDT only. 5-FU was applied to lesions daily for 4 weeks; 29 of 33 (88%) lesions treated with PDT responded completely, compared with 22 of 33 (67%) after 5-FU. After 12 months, two recurrences in the PDT group and six in the 5-FU group reduced complete clinical clearance rates to 82% and 48%, respectively. In the 5-FU group, severe eczematous reactions developed around seven lesions, ulceration in three lesions, and erosions in two lesions, whereas no adverse reactions occurred after PDT.

Table 7. Comparative Studies of Aminolevulinic Acid Photodynamic Therapy (ALA-PDT) and Other Treatment Modalities for the Management of Bowen's Disease
AuthorLocationDosage RegimenResults
  1. FU=fluorouracil; MAL=methyl aminolevulinic acid.

Salim et al.81Face, trunk, and extremitiesComparison of the efficacy of 5-ALA and 5-FU cream.
Pretreatment with 20% ALA for 4 hours before red light illumination; if lesion not clear at 6 weeks, repeat treatment with ALA-PDT was given 100 J/cm2 narrowband red light (630 ± 15 nm).
88% (29/33) of lesions treated with PDT and 67% (22/33) of lesions treated with 5-FU initially responded completely. After 12 months complete clinical clearance rates: 82% for PDT and 48% for 5-FU.
Morton et al.82Face, trunk, and extremitiesComparative trial in 225 patients with 275 Bowen's lesions comparing
2 treatments with MAL-PDT and placebo PDT vs 5-FU topical cream vs 1 treatment with cryotherapy.
At 3 months, the complete response rate were 93% for MAL-PDT, 83% for 5-FU, 86% for cryotherapy; 24-month relapse rates were 18% for MAL-PDT, 21% for 5-FU, and 23% for cryotherapy.
Morton et al.83Face, trunk, and extremitiesComparative trial:
1 treatment with ALA-PDT was compared with 1 treatment of cryotherapy, repeated up to every 2 months, if necessary.
After 1 treatment, complete lesion response rates were 50% for cryotherapy and 75% for ALA-PDT. 100% response achieved after 2 treatments with PDT and 3 treatments with cryotherapy. In 12 months of follow-up, 2 recurrences with cryotherapy and 0 recurrences for ALA-PDT.

Morton and colleagues82 also performed a comparative trial in 225 patients with 275 Bowen's disease lesions comparing two sessions with MAL-PDT relative to placebo PDT, cryotherapy, and topical 5-FU cream. At 3 months, the CR rate was 93% for MAL-PDT, 83% for 5-FU, and 86% for cryotherapy. Twenty-four-month relapse rates were 18% for MAL-PDT, 21% for 5-FU, and 23% for cryotherapy.

In a comparative trial by Morton and colleagues83 of ALA-PDT versus cryotherapy for Bowen's disease, 40 lesions were treated. One treatment with ALA-PDT was compared with one treatment of cryotherapy, repeated up to every 2 months, if necessary. After one treatment, complete lesion response rates were 50% for cryotherapy and 75% for ALA-PDT. After two treatments, lesion response rates were 100% for ALA-PDT; for cryotherapy, the 100% response rate occurred after three treatments. In 12 months of follow-up, two cases of recurrence were seen for cryotherapy and none for ALA-PDT.

Comparative Efficacy of Superficial BCC Versus Bowen's Disease A few studies in the literature compared response rates of Bowen's disease (SCC in situ) with those of superficial BCC (Table 8).84,85 Clearance with PDT was significantly greater for BCC in primary response rates and long-term recurrence rate.

Table 8. Comparative Efficacy of Photodynamic Therapy (PDT) for Basal Cell Carcinoma (BCC) versus Bowen's Disease
AuthorLocationDosage RegimenResults
  1. ALA=aminolevulinic acid; MAL=methyl aminolevulinic acid; AKs=actinic keratoses.

Fink-Puches et al.49Face, scalp, trunk, and extremitiesALA-PDT for superficial BCC vs Bowen's disease.
ALA-PDT applied under occlusion prior exposure to visible light (full spectrum) or different wave bands of polychromatic visible light (full-spectrum visible light, >515, >570, or >610 nm)
Initial response: 86% (82/95) for superficial BCC, 54% (19/35) for Bowen's disease. After a median follow-up of 19 months for BCC and 8 months for Bowen's disease, recurrence rate of 44% (36/81) for BCC and 69% (11/16) for Bowen's disease.
Varma et al.84Face, scalp, trunk, and extremitiesComparative study: ALA-PDT for superficial BCC, Bowen's disease, AKs
light source: Waldmann PDT 1,200, 105 J/cm2 of incoherent red light (center of spectrum at 640 nm)
88 patients with 239 lesions. After 2 treatments, complete clinical clearance in 95% of superficial BCCs, 88% of Bowen's disease, and 99% of AKs. At 12 months, complete response rates: 82% for BCC, 69% for Bowen's disease, and 72% for AKs

In 1998, Fink-Puches and colleagues49 reported the results of a study to measure the primary and long-term clinical and histological clearance rates of PDT for 95 superficial BCCs and 35 superficial SCCs. The complete primary response rate for all wave bands of light was 86% (82/95) for superficial BCCs and 54% (19/35) for superficial SCCs. After a median follow-up of 19 months (range 3–60 months) for BCCs and 8 months (range 3–47 months) for SCCs, the overall recurrence rate was 44% (36/81) for BCCs and 69% (11/16) for SCCs.

Fink-Puches and colleagues49 noted remarkable fibrosis in the deep dermis of superficial BCCs and SCC in situ after ALA-PDT according to histopathology, suggesting that the effect of ALA-PDT reached deeper than the initial depth of invasiveness of the neoplastic tissue. Thus, insufficient penetration of the ALA molecule to the level of the tumor cannot solely explain poorer long-term efficacy of ALA-PDT for nonmelanoma skin cancer observed in this study.

Varma and colleagues84 reported the results of an investigation of the safety and efficacy of a large field light source, with red light wavelengths, to compare the treatment responses of Bowen's disease, superficial BCCs, and AKs. After two treatments, 88% of Bowen's disease lesions, 95% of superficial BCCs, and 99% of AKs showed complete clinical clearance. At 12 months, the CR rates were 69% for Bowen's disease, 82% for superficial BCCs, and 72% for AKs.

Summary of Treatment of Bowen's Disease with PDT In summary, the CR rates for ALA-PDT in Bowen's disease range widely, from initial clearance of 54% to 100% to 12- to 36-month clearance of 31% to 100%.63,73,78–85 The most effective studied light sources include the pulsed dye laser (585–595 nm) and red light wavelengths, both of which were significantly more effective than blue and green wavelengths. PDT for Bowen's disease demonstrated highly variable efficacy at 12 to 36 months of follow-up, which is significantly more variable than that reported for surgical excision with standard margins and Mohs micrographic surgery; thus, surgery is recommended as the treatment of choice for Bowen's disease. Long-term cure rate for other nonsurgical treatment modalities for Bowen's disease are also highly variable. In the largest study reported in the literature, of 617 patients with Bowen's disease, by Thestrup-Pederson and colleagues,85 relapse rates (<5 years) were 34% for cryotherapy, 19% for curettage, 14% for 5-FU, 6% for radiotherapy, and 5% for surgery.

Photorejuvenation

The use of PDT for photorejuvenation is a relatively new application of this technology that has shown promise for reducing the appearance of fine lines and wrinkles, photoaging, telangiectasias, and melasma 13–17,43 (Table 9).

Table 9. Aminolevulinic Acid Photodynamic Therapy (ALA-PDT) for Photorejuvenation
AuthorLocationDosage RegimenResults
  1. IPL=intense pulsed light; AKs=actinic keratoses.

Gold27FaceALA-PDT for AKs and photorejuvenation
blue light source
83% AKs responded, also response in patient's for signs of photoaging: 90% crow's feet, 100% skin roughness, 90% hyperpigmentation, 70% facial erythema.
Ruiz-Rodriguez et al.88FaceALA-PDT-IPL for AKs and photorejuvenation17 patients treated with AKs. At 3 months, 33/38 AKs (86.8%) disappeared with two ALA-PDT treatments using IPL. Qualitative improvement noted in the skin signs of photoaging.
Goldman et al.86FaceALA-PDT-IPL for photorejuvenationImprovement in skin texture, 72%; pigment change, 59%
Avram et al.87FaceALA-PDT-IPL for photorejuvenationImprovement in telangiectasia, 55%; pigment change, 48%; skin texture, 25%

In 2002, Gold and colleagues27 noted early experiences with ALA-PDT with a blue light source in which patients not only had significant AK clearance, but also noticed an overall photorejuvenation effect in adjacent areas of photodamage. Gold and colleagues16 performed a subsequent study with short-contact (30 to 60 minutes) ALA-PDT with blue light; 83% of AKs responded to treatment, and there was a significant response in the signs of photoaging, including improvement in crow's feet (90% of patients), skin roughness (100% of patients), hyperpigmentation (90% of patients), and facial erythema (70% of patients). Goldman and colleagues86 reported similar results with ALA-PDT (1 hour pre-incubation) using blue light as the light source in 32 patients, with improvements in skin texture of 72% and pigmentary change of 59% achieved.

Ruiz-Rodriguez and colleagues88 found that ALA-PDT using IPL as a light source resulted in high levels of clearance of AKs in addition to qualitative improvement in the skin signs of photoaging (wrinkling, coarse skin texture, pigmentation alterations, telangiectases). Seventeen patients with varying degrees of photodamage and AKs were treated with two treatments at a 1-month interval of ALA-PDT-IPL. Ruiz-Rodriguez and colleagues18 more recently published preliminary results on photorejuvenation using MAL and red light.

Comparative Trials for Photorejuvenation: IPL and PDL IPL has been the most effective light source used in conjunction with ALA to improve skin signs of photoaging.13–17,88–91 In five trials,13,14,16,40,90,91 IPL alone was compared with ALA-IPL-PDT (Table 10); ALA-IPL-PDT resulted in significantly greater improvements in the skin signs of photoaging, including AK clearance, crow's feet, tactile skin roughness, dyspigmentation, skin mottling, and erythema. Similarly, in a split-face trial by Key and colleagues,89 ALA-PDL was found to result in greater improvement in photorejuvenation than PDL alone. Marmur and colleagues90 performed a split-face comparison, performing an ultrastructural analysis of collagen production before and after treatment with ALA-PDT-IPL versus IPL alone. The authors reported an increase in type I collagen when pretreatment with ALA was performed before IPL, possibly suggesting a mechanism whereby PDT mediates improvement in skin laxity and texture.

Table 10. Comparative Trials of Photoaging: Intense Pulsed Light (IPL) and Photodynamic Therapy (PDL) vs Aminolevulinic Acid (ALA)-PDT-IPL and ALA-PDT-Pulsed Dye Laser (PDL)
AuthorLocationDosage RegimenResults
Alster et al.13FaceALA-PDT-IPL vs IPL for photorejuvenationALA-PDT IPL side: higher clinical scores for photorejuvenation vs IPL alone
Dover et al.14FaceALA-PDT-IPL vs IPL for photorejuvenationImprovement in global photoaging scale: 50% for IPL alone, 80% for ALA-IPL-PDT. Hyperpigmentation: 65% for IPL alone, 95% for ALA-IPL-PDT. Fine lines: 20% for IPL alone, 55% for ALA-IPL-PDT.
Gold et al.16FaceALA-PDT-IPL vs IPL alone for actinic keratoses and photodamage13 patients. Photodamage indicators: crow's feet: 55% ALA-PDT-IPL, 28.5% IPL alone. Tactile skin roughness: 55% ALA-PDT-IPL, 29.5% IPL alone. Mottled hyperpigmentation: 60.3% ALA-PDT-IPL, 37.2% IPL alone. Erythema: 84.6% ALA-PDT-IPL, 53.8% IPL alone.
Key et al.89FaceALA-PDL-PDT vs PDL alone for photorejuvenationALA-PDL more significant than PDL alone for photorejuvenation
Marmur et al.90FaceALA-PDT-IPL vs IPL for photorejuvenationOn ultrastructural analysis, greater increase in type I collagen when pretreated with ALA than with IPL alone.
Zane et al.40FaceMAL-PDT for photorejuvenation. MAL under occlusion for 3 hours+red light (37 J/cm2)Improvement noted in photoaging with PDT; mottled hyperpigmentation, fine lines, roughness, and sallowness of the skin showed signs of improvement.
According to echocardiography, improvement in skin thickness and pixel count and area and reduction in subepidermal low-echogenic band thickness

Zane and colleagues40 recently reported a novel mechanism for evaluating the effects of PDT on skin thickness using echocardiography. They also used high-resolution echocardiography to observe changes in skin thickness and found an increase in skin thickness and pixel count and area and a reduction in subepidermal low-echogenic band thickness.

Summary of Photorejuvenation with PDT A number of studies evaluating treatment of AKs with PDT identified improvements in background skin in the signs of photoaging, specifically improvement in rhytides, skin roughness, hyperpigmentation, and erythema. A critical study by Marmur and colleagues90 identified an increase in type I collagen production associated with ALA-PDT using IPL. Additionally, photosensitizer activation of specific molecular pathways and a nonspecific immune response may mediate photorejuvenation. Additional understanding of the laser–tissue interactions at the molecular level in PDT is crucial in advancing this technology and in selecting patients who will benefit from this therapy.

Skin Cancer Prevention and Treatment in Transplant Patients

Transplant recipients have a high risk for widespread epithelial neoplasms of the skin.91,92 Thus, there is a need to treat initial stages of these neoplasms, such as AKs and Bowen's disease, more aggressively to prevent progression to invasive SCC.

Several investigators have explored the chemopreventive capacity of PDT, particularly in preventing skin cancer in transplant patients, who have been proven to have up to a 50 times greater risk of SCC post-transplantation. Wulf and colleagues93 reported the results of an open intrapatient randomized study investigating the prevention potential of PDT in 27 renal transplant patients with AKs and other skin lesions in two circular contralateral areas (each 5 cm in diameter). The treatment surface area was débrided, and MAL cream (160 mg/g) was applied for 3 hours before illumination using non-coherent red light. The control area received no treatment. The mean time to occurrence of the first new lesions was significantly longer in treated than control areas (9.6 vs 6.8 months). Over 12 months, 62% (16/26) of treated areas were free from new lesions, compared with 35% (9/26) in control areas.

Dragieva and colleagues94 reported the results of PDT with the use of MAL in combination with visible light in transplant patients. To evaluate the efficacy and tolerability of MAL-PDT versus placebo in the treatment of AKs in transplant recipients, 17 transplant recipients with a total of 129 AKs were enrolled. The lesional areas treated with MAL were clinically cleared in 13 of 17 patients at 16 weeks. No reduction in the size or number of AKs was observed placebo-PDT-treated areas. Adverse events, such as erythema, edema, and crust formation, were mild to moderate, and all patients tolerated treatment well.

In a subsequent study by Dragieva and colleagues,95 20 transplant recipients and 20 controls with histologically confirmed AKs or Bowen's disease underwent a single or two consecutive treatments of topical PDT. The application of 20% ALA for 5 hours was followed by illumination with visible light. The overall CR rates at 4, 12, and 48 weeks were 86%, 68%, and 48%, respectively. The cure rates in both patient groups were comparable at 4 weeks, but were significantly lower in transplant recipients than in controls at 12 and 48 weeks (p<.05).

In a study by Perrett and colleagues,96 a comparison of topical MAL-PDT with topical 5-FU cream in the treatment of post-transplantation epidermal dysplasia was performed. Treatment with two cycles of topical MAL-PDT 1 week apart was randomly assigned to one area of epidermal dysplasia, and 5-FU cream was applied twice daily for 3 weeks to a clinically and histologically comparable area. Patients were assessed 1, 3, and 6 months after treatment. At all time points evaluated, PDT was more effective than 5-FU in achieving complete resolution; eight of nine lesional areas cleared with PDT (89%), compared with one of nine lesional areas treated with 5-FU (11%, p=.02). The mean lesional area reduction was also proportionately greater with PDT than with 5-FU (100% vs 79%).

Conclusions

PDT has demonstrated excellent promise as a treatment for premalignant and malignant skin cancers and photorejuvenation and cosmetic nonablative resurfacing. Perhaps most importantly, whereas PDT achieves a similar rate of clearance for common conditions, such as AKs, it is better tolerated than standard treatment modalities (5-FU cream, imiquimod cream, liquid nitrogen, surgical excision) and has advantages of excellent cosmetic outcomes and improvement of background photodamage. Further indicating the success and treatment popularity of PDT, in a recent clinical study reported by our group,97 patients ranked PDT as the most preferred treatment for AKs. In addition, a recent study by Gold and colleagues suggests that ALA-PDT is the most cost-effective field treatment therapy for patients with diffuse AKs.98 Particularly in patients highly susceptible to nonmelanoma skin cancer, such as patients with NBCCS, patients with large areas of actinic damage, and patients who have undergone organ transplantation or systemic immunosuppressive therapy, this technique represents an ideal approach to treatment and chemoprevention for precancers and nonmelanoma skin cancer lesions.

Ancillary