Chemoprevention Utilizing ALA–PDT

| November 30, 2008
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Therapeutic and Aesthetic Uses of Photodynamic Therapy

Part three of a five-part series

by Michael H. Gold, MD

Medical Director, Gold Skin Care Center and The Laser & Rejuvenation Center, Nashville, Tennessee


Disclosure: Dr. Gold is a consultant to, speaks for, and receives honoraria from DUSA Pharmaceuticals. Dr. Gold is also a consultant to Galderma and performs research on its behalf.

Abstract

The use of aminolevulinic acid photodynamic therapy and methyl ester of aminolevulinic acid photodynamic therapy has become commonplace in dermatology for the treatment of actinic keratoses, among other clinical entities. An intriguing question that has arisen is whether we can utilize these medicines for a chemopreventive effect; that is, preventing or delaying the onset of actinic keratoses and perhaps nonmelanoma skin cancers. This manuscript reviews the current literature and anecdotal evidence that suggests that aminolevulinic acid photodynamic therapy and methyl ester of aminolevulinic acid photodynamic therapy may indeed be chemopreventive and thus useful in preventing and/or delaying these lesions.

(J Clin Aesthetic Derm. 2008;1(4):26–32)

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Over the past several years, we have seen an increase in the use of aminolevulinic acid (ALA) photodynamic therapy (PDT) to treat a variety of conditions that are of concern to the dermatologic community. In previous manuscripts, we have reviewed the use of ALA-PDT in the treatment of actinic keratoses (AKs) and photorejuvenation1 as well as the treatment of inflammatory acne vulgaris.[2] More dermatologists are utilizing ALA-PDT for these skin conditions than ever before, and ALA-PDT has become a standard part of the dermatologic armamentarium for many dermatologists across the country.

Through personal anecdotes from a number of investigators, there is another potential indication that is beginning to emerge for the use of PDT in clinical practice. That is, using PDT as a chemopreventive agent in the prevention of AKs and possibly nonmelanoma skin cancers. The purpose of this manuscript is to relay the clinical information that has been made available and gives many of us hope that someday utilizing PDT as a chemopreventive agent will be a reality.

CHEMOPREVENTIVE AGENTS

Chemoprevention is defined as the use of a topically applied or oral agent from either a dietary source or a pharmacologic agent that can inhibit or reverse the development of cancer.[3] With regard to AKs and nonmelanoma skin cancers, we know that the first step in their development is exposure to ultraviolet light. Obviously, sun avoidance and the use of appropriate sunscreens have been shown to minimize, but not totally prevent, the risk of developing AKs and skin cancer later in life. Although many of us receive a great deal of sun exposure early in life, numerous factors are responsible for the eventual development of skin cancer later in life, with the average age of development of basal cell carcinomas being 69 years of age and that of squamous cell carcinoma being 75 years of age. These factors are beyond the scope of this manuscript. Known dermatologic chemopreventive agents in dermatology include vitamin-A derivatives, such as retinoids. There are studies in the literature that support the use of vitamin-A derivatives in selected individuals as a chemopreventive agent. Again, it is beyond the scope of this manuscript to review all of the clinical trials that support the use of retinoids in the prevention of skin cancer, but several well-written manuscripts are available.[4–9]

Some agents have been looked at as potential chemopreventive agents in dermatology including difluoromethylornithine; T4 endonuclease V; nonsteroidal, anti-inflammatory agents; polyphenolic antioxidants including green tea and grape seed; silymarin; isoflavone genistein; curcumin; and lycopene. Other agents including vitamin E, beta-carotene, and selenium have been proven not to be chemopreventive in nature.[3]

PHOTODYNAMIC THERAPY—EARLY EVALUATIONS

There are currently two Food and Drug Administration (FDA)-approved medicines available in the United States for use with PDT. The first drug that was approved is known as Levulan® Kerastick™ (DUSA Pharmaceuticals, Wilmington, Massachusetts), a 20% 5-ALA solution that is best used with a blue light source, most commonly the BluU® (Dusa Pharmaceuticals, Wilmington, Massachusetts) (Figure 1 and Figure 2). Many clinical investigations have shown that besides blue light, a variety of lasers and light sources can be utilized for PDT, as shown in Figure 3. The FDA indication for the use of ALA-PDT is for the treatment of nonhyperkeratotic AKs of the face and scalp following a 14- to 18-hour drug incubation utilizing a blue light source for 16 minutes and 40 seconds.10 Clinical investigations have documented that the standard use of ALA-PDT in the United States today is by using short-contact (about one hour), full-face therapy and one of the many light sources that is known to activate ALA (Figure 3).[1,11–13]

The second drug to be FDA approved for use in PDT is known as Metvixia (PhotoCure ASA, Oslo, Norway; Galderma, Fort Worth, Texas) in the United States. This is the methyl ester of ALA (MAL) and has been studied extensively in Europe and elsewhere where it is known as Metvix (Galderma, Fort Worth, Texas) (Figure 4). It is well known for its effectiveness in treating nonmelanoma skin cancer and has also shown effectiveness in the treatment of AKs and photorejuvenation.[14–17] It has European Union approval for the treatment of nonhyperkeratotic AKs and nonmelanoma skin cancers, which are not amenable to conventional therapy. It is best utilized with a red light source, known as the Aktilite (PhotoCure ASA, Oslo, Norway; Galderma, Fort Worth, Texas) (Figure 5). Most clinicians recommend that MAL be used under occlusion for three hours before red light therapy. Most also recommend two treatments for nonmelanoma skin cancer at one-week intervals for best potential clearances. In the United States, Metvixia is FDA approved for the treatment of nonhyperkeratotic AKs, again utilized with a red light source. Further clinical investigations, currently underway, will help determine the optimal methods for using Metvixia in the United States, as experience by most clinicians is limited.

Early on, a group of dermatologists found, through anecdotal evidence, that PDT had some effect on chemoprevention. In 2002, the author of this paper published one of the first off-label clinical works on the use of ALA in the treatment of photodamaged skin.[18] The article reviewed several clinical examples that utilized ALA-PDT in patients with AKs and a history of nonmelanoma skin cancer. The patients in this manuscript received ALA-PDT as per the original FDA protocol. Clearance of AKs was achieved in these patients after a series of treatments, ranging from 2 to 4, over a 2- to 4-month period of time. Of interest, the author’s father was one of the patients, who was also one of the first US patients to receive ALA-PDT after its FDA approval. He had been coming to the author’s office for many years to have skin cancer removed from his skin—specifically the face and scalp areas. Routine surgical excision of these nonmelanoma skin cancers was the norm for one of his typical visits. After the induction of ALA-PDT and through twice-yearly maintenance treatments, the author’s father was free of skin cancer over the next seven years (Figures 6a&6b). And since his last skin cancer, the incidence of new or recurrent skin cancer has dramatically decreased. In the past four years, he has only had three new cancers, down from 3 to 5 skin cancers removed per visit.

At about the same period of time, another colleague of the author’s treated his father as well, as shown in Figures 7a & 7b. His father had diffuse actinic damage and numerous AKs at the time of his first ALA treatment. For over the next three years, the treated areas remained disease free, something that was not common, given his father’s past history of multiple AKs requiring multiple different treatment modalities (personal communication with M Braun).

Many of us have questioned whether ALA-PDT or MAL-PDT could be utilized as a chemopreventive agent, which is why much more rigorous clinical work is required in order to grasp the concept more fully. Several clinical investigations, both in the laboratory and in patients, have begun looking at this potentially exciting indication for PDT.

CLINICAL TRIALS OF PDT FOR CHEMOPREVENTION

In 2004, in one of the first human clinical trials on the subject of chemoprevention, Dragieva et al[19] looked at topical PDT in the treatment of AKs and Bowen’s disease (squamous cell carcinoma in situ) in transplant patients. Twenty transplant patients and 20 control individuals were entered into this clinical trial with biopsy-confirmed AKs or Bowen’s disease. Patients received either one or two ALA-PDT treatments utilizing a five-hour drug incubation followed by illumination with 75J/cm2 of visible light delivered at 80mW/cm2 by an incoherent light source. The complete cure rates among the two groups were comparable at four weeks post the last treatment, but statistically significantly less in the transplant population at 12 weeks and 48 weeks. Side effects from the procedure were erythema, edema, and crust formation following the light therapy. Cosmetic appearances as a result of treatment were very good. The authors concluded that PDT was a safe and effective treatment for AKs and Bowen’s disease in immunosuppressed transplant patients with initial response rates similar to those in immunocompetent patients (see summary of clinical trials in Table 1).

Also in 2004, Bissonnette et al[20] looked at the application of ALA in hairless mice where ALA was applied weekly in these animals. The mice received weekly ALA application alone, blue light alone, or ALA-PDT using blue light for a total of 10 months followed by an additional two months of observation. The mice were examined weekly for the development of skin tumors; none were found during the treatment period or during the observation time period. Caty et al21 in 2006 examined large-surface MAL on transgenic mice—mice that produce basal cell carcinoma when exposed to ultraviolet (UV) light. Thirty-five mice were exposed to weekly UV irradiation for a total of 20 weeks. The first group (n=20) was only exposed to UV light; whereas, the second group (n=15) received UV exposure and weekly MAL-PDT treatments. The mice were sacrificed at 28 weeks and the skin examined histologically. Results showed that 19 mice in Group 1 and no mice in Group 2 developed basal cell carcinoma (p=0.001). The authors concluded that topical MAL was able to delay the development of microscopic basal cell carcinoma when chronically exposed to UV irradiation.

Itkin and Gilchrest22 have looked at ALA-PDT in preventing or delaying skin cancer development in patients suffering from basal cell nevus syndrome. Two patients with basal cell nevus syndrome were evaluated with ALA-PDT and a blue light source. The affected areas were treated with ALA, which was incubated on the skin for 1 to 5 hours and then illuminated for 16 minutes and 40 seconds. Each patient received two treatments at intervals of 2 to 4 months and final assessments were made eight months after the initial treatment.

Complete clinical responses were noted in eight of nine (89%) superficial basal cell carcinomas, five of 16 (31%) nodular basal cell carcinomas on the face, and 18 of 27 (67%) of superficial basal cell carcinomas on the lower extremities. The remaining 21 basal cell carcinoma lesions present showed partial clinical resolution. No new basal cell carcinomas were noted to develop in the treatment areas during the eight-month observation period. The lesions that responded to therapy did so with an excellent cosmetic appearance. Pain during light illumination was the only significant adverse event noted during the treatments. A second clinical evaluation by Chapas and Gilchrest23 described a single patient with basal cell nevus syndrome treated with ALA-PDT every 2 to 3 months for a total of four treatments. The treatments resulted in a reduction in the number and size of existing basal cell carcinomas, improving the appearance of previous surgical scars and decreasing the rate of tumor development. ALA-PDT may become a recognized therapy for those suffering from basal cell nevus syndrome, as witnessed by these two clinical evaluations.

Tschen et al[24] looked at a 12-month follow-up in patients treated with ALA-PDT for AKs. One hundred and one patients with at least 12 discrete AKs were enrolled in this clinical trial. The complete clearance noted after one ALA-PDT treatment was 76 percent and 72 percent at one and two months following therapy. Of the 60 percent of individuals who received a second treatment, 86 percent were found to have complete AK clearance at four months, with this number gradually decreasing to 78 percent by Month 12. The overall recurrence rate of AKs in this clinical trial was found to be 24 percent. The authors concluded that ALA-PDT was useful in treating AKs and was also useful in delaying the development of new AKs in this patient population.

In 2006, de Graaf et al[25] published a paper in which they noted that PDT did not prevent the development of squamous cell carcinoma in organ-transplant recipients. Forty transplant patients were evaluated over a two-year period for the development of squamous cell carcinoma and keratotic skin lesions. Each of the patients had a single PDT treatment and was followed every three months for the following two years. The treatment area consisted of one forearm and hand where the contralateral side was utilized as a control. At the end of the two-year evaluation period, there was no statistically significant difference in the development of squamous cell carcinomas (15 squamous cell carcinomas in 9 of 40 PDT-treated arms and 10 squamous cell carcinomas in 9 of 40 control arms). The number of keratotic lesions increased in both groups, but was less pronounced among the PDT-treated group. Nearly 80 percent of the patients reported mild-to-severe adverse effects, mainly pain and a burning sensation during the treatment illumination.

Several recent European groups have also looked at the potential role of PDT as a chemopreventive agent. Wulf et al[26] reported on an intrapatient-controlled clinical trial in 27 renal transplant patients with AKs and other skin lesions. The treatment areas were prepared and treated as to the routine protocols for MAL-PDT; the controlled side was not treated. The mean time to occurrence of the first new AK lesion was significantly longer in those treated with MAL-PDT than in the control group (9.6 months vs. 6.8 months, p=0.034). Over 12 months, 62 percent (16/26) of the treated areas were free from AKs compared with 35 percent (9/26) in control areas. This study suggests the effectiveness of MAL-PDT in the prevention of AKs in immunocompromised, renal transplant patients. In a second ongoing clinical trial, Wennberg et al[27] is evaluating 81 transplant patients in a multicenter clinical trial. The areas under investigation include being treated with MAL-PDT or cryotherapy. At press time, the number of AKs developing in the MAL-PDT group is less than those in the cryotherapy group.

Nestor et al[13] reported on a group of patients followed by the lead author in which there were 72 facial nonmelanoma skin cancers found in five patients over a three-year period, equating to 5.2 nonmelanoma skin cancers per patient per year. These five patients were treated with ALA-PDT with either a blue light source or an intense pulsed light source. Over the course of the next two years, only 11 facial nonmelanoma skin cancers were found (1.3 per patient per year). It was concluded that the use of ALA-PDT in this patient population was effective for chemoprevention of facial nonmelanoma skin cancers (Figure 8).

Finally, work by Lee has convinced many in the United States that chemoprevention is very relevant for ALA-PDT. In a first evaluation, 25 immunocompromised transplant patients were studied along with 25 nonimmuno-compromised patients looking at AK formation over a two-month period. He found 90 percent of the nonimmunocompromised patients and 75 percent of the immunocompromised patients did not develop AKs. In a second observation, 12 transplant patients were treated with repeated, cyclic PDT therapy every 4 to 8 weeks for 6 to 14 total treatments. The treated areas were on the arms. Evaluations included the number of squamous cell carcinomas on the arms in the preceding 12 months before therapy compared to the number of squamous cell carcinomas that developed over the next 24 months. He found that, on average, patients were developing 3.3 squamous cell carcinomas per month per patient. After the cyclic PDT therapy, patients were found to develop only 0.20 squamous cell carcinomas per month per patient. The ALA incubation was one hour in these patients who were treated with blue light. The treatments were found to be safe and effective in reducing the number of squamous cell carcinomas in this patient population and warrant further evaluation in the future (personal communication with P Lee).

Conclusion

All of these studies warrant further evaluation to determine if ALA-PDT and MAL-PDT are indeed true chemopreventive agents. If these investigations all lead to the conclusion that this is so, additional well-defined and well-organized clinical trials are needed.

References

1.    Gold MH. The treatment of actinic keratoses and photorejuvenation utilizing photodynamic therapy. J Clin Aesthetic Derm. 2008;1(2);32–37.

2.    Gold MH. Lasers and light treatments for acne vulgaris— promising therapies. J Clin Aesthetic Derm. 2008;1(3):28–34.

3.    Wright TI, Spencer JM, Flowers FP. Chemoprevention of nonmelanoma skin cancer. J Am Acad Dermatol. 2006;54(6):933–946.

4.    Lebwohl M, Menter A, Koo J, et al. Case studies in severe psoriasis: a clinical strategy. J Dermatolog Treat. 2003;14(suppl 2):3–6.

5.    Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol. 1995;13:1933–1938.

6.    de Sévaux RG, Smit JV, de Jong EM et al. Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin. J Am Acad Dermatol. 2003;49:407–412.

7.    Smit JV, de Sévaux RG, Blokx WA, et al. Acitretin treatment in (pre)malignant skin disorders of renal transplant recipients: histologic and immunohistochemical effects. J Am Acad Dermatol. 2004;50:189–196.

8.    De Graaf YG, Euvrard S, Bouwes Bavinck, et al. Systemic and topical retinoids in the management of skin cancer in organ transplant recipients. Dermatol Surg. 2004;30(4 pt 2):656–661.

9.    Buccheri L, Katchen BR, Karter AJ, Cohen SR, et al. Acitretin therapy is effective for psoriasis associated with human immunodeficiency virus infection. Arch Dermatol. 1997;133:711–715.

10.    Jeffes EW, McCullough JL, Weinstein GD, et al. Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light. J Am Acad Dermatol. 2001;45(1):96–104.

11.    Dover JS, Bhatia AC, Stewart B, et al. Topical 5-aminolevulinic acid combined with intense pulsed light in the treatment of photoaging. Arch Dermatol. 2005;141(10): 1247–1252.

12.    Gold MH, Bradshaw VL, Boring MM, et al. Split-face comparison of photodynamic therapy with 5-aminolevulinic acid and intense pulsed light versus intense pulsed light alone for photodamage. Dermatol Surg. 2006;32(6): 795–801.

13.    Nestor MS, Gold MH, Kauvar AN, et al. The use of photodynamic therapy in dermatology: results of a consensus conference. J Drugs Dermatol. 2006;5(2): 140–154.

14.    Pariser DM, Lowe NJ, Stewart DM, et al. Photodynamic therapy with topical methyl aminolevulinate (Metvix®) is effective and safe in the treatment of actinic keratosis: results of a prospective randomized trial. J Am Acad Dermatol. 2003;48:227–232.

15.    Morton C, Campbell S, Gupta G, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol. 2006;155(5):1029–1036.

16.    Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol. 2007;56:125–143.

17.    Zane C, Capezzera R, Sala R, Venturini M, Calzavara-Pinton P. Clinical and echographic analysis of photodynamic therapy using methylaminolevulinate as sensitizer in the treatment of photodamaged facial skin. Lasers Surg Med. 2007;39(3):203–209.

18.    Gold MH. The evolving role of aminolevulinic acid hydrochloride with photodynamic therapy in photoaging. Cutis. 2002;69(6 Suppl): 8–13.

19.    Dragieva G, Hafner J, Dummer R, et al. Topical photodynamic therapy in the treatment of actinic keratoses and Bowen’s disease in transplant recipients. Transplantation. 2004; 77(1):115–121.

20.    Bissonnette R, Bergeron A, Liu Y. Large surface photodynamic therapy with aminolevulinic acid: treatment of actinic keratoses and beyond. J Drugs Dermatol. 2004;3:S26–S31.

21.    Caty V, Liu Y, Viau G, et al Multiple large surface photodynamic therapy sessions with topical methyl aminolevulinate in PTCH heterozygous mice. Br J Derm. 2006;154:740–742.

22.    Itkin A, Gilchrest BA. delta-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome. Dermatol Surg. 2004;30: 1054–1061.

23.    Chapas AM, Gilchrest BA. Broad area photodynamic therapy for treatment of multiple basal cell carcinomas in a patient with nevoid basal cell carcinoma syndrome. J Drugs Dermatol. 2006;5(2 Suppl):3–5.

24.    Tschen EH, Wong DS, Pariser DM. Photodynamic therapy using aminolaevulinic acid for patients with nonhyperkeratotic actinic keratoses of the face and scalp: phase IV multicentre clinical trial with 12-month follow up. Br J Dermatol. 2006;155(6):1262–1269.

25.    de Graaf GL, Kennedy C, Wolterbeek R et al. Photodynamic therapy does not prevent cutaneous squamous-cell carcinoma in organ-transplant recipients: results of a randomized-controlled trial. J Invest Dermatol. 2006;126(3):569–574.

26.    Wulf HC, Pavel S, Stender I, et al. Topical photodynamic therapy for prevention of new skin lesions in renal transplant recipients. Acta Derm Venereol. 2006;86(1):25–28.

27.    Wennberg AM, Keohane S, Lear JT, et al. (MAL-PDT) cream in immunocompromised organ transplant recipients with nonmelanoma skin cancer. Presented at: 10th World Congress on Cancers of the Skin; May 13-16, 2005; Vienna, Austria.

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Category: 11-2008 (November 2008), Photdynamic Therapy, Special Series

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