Evaluating the safety and efficacy of aminolevulinic acid 20% topical solution activated by pulsed dye laser and blue light in the treatment of facial cutaneous squamous cell carcinoma in situ

Squamous cell carcinoma (SCC) is the second most common cutaneous malignancy, after basal cell carcinoma (BCC). Photodynamic therapy (PDT) involves converting a photosensitizer to reactive oxygen intermediates, which preferentially bind to hyperproliferative tissue. The most commonly used photosensitizers are methyl aminolevulinate and aminolevulinic acid (ALA). Presently, ALA‐PDT is approved in the US and Canada for the treatment of actinic keratoses on the face, scalp, and upper extremities.


| INTRODUC TI ON
The incidence of skin cancers in the United States surpasses all other cancers combined, imposing a significant burden on the public health system. 1 Cutaneous squamous cell carcinoma (SCC) is the second most frequent keratinocyte-derived malignancy after basal cell carcinoma (BCC). 2 Compared with BCC, SCC has lower prevalence but is associated with a higher mortality rate due to the risk of metastasis. 1 Risk factors for developing SCC include ultraviolet (UV) light exposure, chronic inflammation, environmental exposure (e.g., arsenic), infection (e.g., human papillomavirus), and immunosuppression. 2 Photoprotection, avoidance of tanning beds, and nicotinamide are effective preventive methods. 3,4 Actinic keratoses (AKs), which present as erythematous papules or plaques, are considered a precursor of SCC. 5 Actinic keratosis, squamous cell carcinoma in situ (isSCC), and invasive SCC are thought to represent steps of progression to squamous neoplasia. 6 There are many treatment options for SCC. Surgery, including Mohs micrographic surgery (MMS), is the gold standard. 7 Nonsurgical options for invasive SCC include topical chemotherapy, radiotherapy, and immunotherapy. Systemic chemotherapy is reserved for metastatic disease. Another potential option for SCC treatment is photodynamic therapy (PDT), which utilizes a photosensitizer that is activated by a specific wavelength and energy of light to generate reactive oxygen intermediates. 8 Photodynamic therapy is widely used in dermatologic and oncological practices as a treatment for AK, superficial nonmelanoma skin cancer (NMSC), and acne vulgaris. 8,9 Several retrospective reviews and prospective trials demonstrated the efficacy of PDT for managing isSCC and SCCs, with excellent cosmesis. [10][11][12][13][14] When aminolevulinic acid (ALA) is absorbed into the skin, it is converted intracellularly to its active form, protoporphyrin IX (PpIX). 8 PpIX has a high affinity for pilosebaceous units, dysplastic cells, and hyperproliferative tissues, and it can be activated by a variety of laser and light sources. 8,15 In the US and Canada,

| Patient selection
Twenty patients with clinically observable and biopsy-confirmed isSCC on the face were recruited. The diagnostic biopsy must have been performed within 6 months of recruitment, and the lesion not previously treated. Only lesions with a diameter of 0.4-1.3 cm were considered for the study, and patients with infiltrative, severe metaplastic, or recurrent isSCC were excluded.

| Assessments
Surgical excision was performed 4-6 weeks after the second treatment for histopathological assessment, which was performed by a

| Outcomes
The primary endpoint was the proportion of patients who achieved histological clearance of isSCC at the end of treatment (EOT). The secondary endpoint was the proportion of patients with CC of the skin lesion.

| Patient characteristics
Twenty patients with Fitzpatrick skin type II or III and a mean age

| Pigmentation assessments
No patients had any lesional pigmentation changes throughout the study.

| Local skin reactions
Median LSRs peaked within 1 week after each PDT and blue light treatment (Visits 3 and 7; Table 1). As expected, LSRs steadily de-

| Tolerability assessment
The mean pain score recorded by patients on the VAS within 15 minutes after each blue light illumination was 2.95 (range, 0-10; SD, 2.97).

| Safety
The majority of patients (n = 13, 65%) did not report any adverse events (AEs) throughout the study period. None of the reported AEs were serious. Reported AEs include allergic contact dermatitis around the treatment site, allergic contact dermatitis distant from the treatment site, blurry vision, right ear pain, right leg cellulitis, double vision, hypotension, and wound site infection. None of the AEs were considered by the investigators to be related to the study treatment, and treatment administration was not altered due to any of the aforementioned AEs. None of the patients withdrew from the study for any reason.

| DISCUSS ION
Presently, ALA-PDT is not approved by the United States Food and Drug Administration for the treatment of isSCC. One of the obstacles to interpreting published data is the lack of a generalized treatment TA B L E 1 Median local skin reaction scores for the lesion areas. (>20 mm in diameter) isSCC patches in 38 patients (2 with two lesions each, 36 with one lesion each), lesion size was associated with clearance rate; the 12-month clearance rate after 1-3 treatments was 78%, and larger lesions were more likely to require multiple treatment sessions or to persist despite treatment. 18 Treatment with 1-2 sessions of ALA-PDT was also highly effective in a separate cohort of 10 patients with 45 patchy isSCC lesions (12-month clearance rate, 89%), but lesion site in this cohort was not associated with clearance.
A randomized trial of ALA-PDT with red light delivered as a single or a twofold illumination scheme (treatment at 4 h or both 4 and 6 h after ALA application, respectively) in 40 patients with 50 isSCC patches reported a 12-month CR rate of 80% in the single-illumination group compared with an 88% CR in the twofold illumination group, although the difference was not statistically significant. 17 In our study, we used the PDL to activate the photosensitizer before conventional PDT. Our results are consistent with other published literature with regard to histological clearance, CC, and safety profile. The efficacy observed may be attributed in part to study design elements including diameter <2.0 cm, incubation time >4 h, and lesions located on the face that were associated with treatment success in other studies. 16 Histological analysis revealed treatment failure in three patients. One of these patients had a multifocal isSCC on the left inferior lateral malar cheek, and treatment failure may be explained by the fact that the PDT sessions failed to treat the peripheral margins of the lesion, leaving behind residual isSCC.
Another treatment failure occurred on the right superior ear helix.
We hypothesize that the PDT was ineffective in this area due to the crumpled surface of the helix.
Another option for treatment of isSCC is MMS, which is the current mainstay treatment for NMSC on the face. The 5-year cure rates for primary and recurrent BCCs and SCCs treated with MMS are over 90%. 19 Although this cure rate is higher than observed in the current study, the finding of decreasing LSR at EOT compared to screening supports the cosmetic superiority of PDT over other options. Photodynamic therapy can be used to treat isSCC without the scarring associated with surgical treatments.

| CON CLUS ION
In this study, ALA-PDL-PDT was a well-tolerated and safe treatment option for small isSCC on the face. It was highly efficacious and pro-

ACK N OWLED G M ENTS
Research funding for the study was provided by Sun Pharma. Medical writing and editorial support were provided by Hilary Durbano, PhD, and Dana Lengel, PhD, of AlphaBioCom, a Red Nucleus company, and funded by Sun Pharma.

CO N FLI C T O F I NTER E S T S TATEM ENT
MN reports research grants from Sun Pharma. HH, FC, AL, and AG report nothing to disclose.

DATA AVA I L A B I L I T Y S TAT E M E N T
Research data are not shared.
F I G U R E 1 Imaging of isSCC in two patients obtained (A) before and (B) after treatment with ALA-PDL-PDT. ALA, aminolevulinic acid; PDL, pulsed dye laser; PDT, photodynamic therapy; isSCC, squamous cell carcinoma in situ.

E TH I C S S TATEM ENT
The study protocol was approved by the United States Institutional