Representative microinvasive squamous cell carcinoma lesions on the left cheek after treatment with ablative fractional laser-assisted photodynamic therapy.
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Choi S, Kim K, Song K. Effect of Methyl Aminolevulinate Photodynamic Therapy With and Without Ablative Fractional Laser Treatment in Patients With Microinvasive Squamous Cell Carcinoma: A Randomized Clinical Trial. JAMA Dermatol. 2017;153(3):289–295. doi:10.1001/jamadermatol.2016.4463
Is photodynamic therapy with and without ablative fractional laser effective in the treatment of microinvasive squamous cell carcinoma?
In this randomized clinical trial that included 45 patients randomized to treatment with a single ablative fractional laser-primed photodynamic therapy session vs 2 conventional sessions without ablative fractional laser. The proportion achieving long-term complete response of photodynamic therapy was 68.4% with ablative fractional laser vs 14.3% without ablative fractional laser.
Photodynamic therapy with ablative fractional laser could be a good alternative treatment option for microinvasive squamous cell carcinoma.
Surgical excision is the standard treatment for cutaneous squamous cell carcinoma (SCC). However, microinvasive SCC (Clark level II) is limited to the papillary dermis, and it should be differentiated from invasive SCC. Ablative fractional laser-primed photodynamic therapy (AFL-PDT) may have enhanced efficacy.
To compare 1 session of AFL-PDT with 2 sessions of conventional methyl aminolevulinate-PDT (MAL-PDT) for the treatment of microinvasive SCC.
Design, Setting, and Participants
A 2-armed, randomized, single-blind, comparative trial of 45 patients with histologically proven microinvasive SCC. Twenty-one patients were randomized to treatment with a single AFL-PDT session, and 24 patients were randomized to 2 MAL-PDT sessions with a 1-week interval between sessions using a computer-generated program. Standard pretreatment such as curettage was not performed prior to PDT owing to a tendency to bleed. The efficacy, recurrence rate, cosmetic outcomes, and safety were assessed 1 week, 3, 12, and 24 months after the last treatment.
AFL was performed with an ablation depth of 550 µm to 600 µm, coagulation level of 1, treatment density of 22%, and a single pulse. Then, MAL cream was applied under occlusion for 3 hours and illuminated by using a red light-emitting diode light at 37 J/cm2. A second session of MAL-PDT was administered after 7 days.
Main Outcomes and Measures
The primary outcome measures were the lesion response at 3 and 12 months, and the recurrence rate 12 months after the last treatment.
Twenty-one patients (6 men, 15 women) with a mean (SD) age of 76 (6) years were randomized to treatment with a single AFL-PDT session, and 24 patients (11 men, 13 women) with a mean (SD) age of 75 (6) years were randomized to 2 MAL-PDT sessions. The overall complete response rates 3 months after treatment were 84.2% with AFL-PDT and 52.4% with MAL-PDT (P = .03). These differences in efficacy remained significant at the 24-month follow-up. The recurrence rate was significantly lower with AFL-PDT (12.5%) than with MAL-PDT (63.6%) at 24 months (P = .006). AFL-PDT and MAL-PDT did not differ significantly with respect to the cosmetic outcomes, adverse events, or pain intensity.
Conclusions and Relevance
AFL-PDT can be used as an alternative treatment option for patients with microinvasive SCC who are not suitable for surgical treatment.
clinicaltrials.gov Identifier: NCT02666534
Squamous cell carcinoma (SCC) lesions are potentially metastatic and can be life threatening. Hence, surgical excision is the standard treatment for cutaneous SCC.1 However, some patients are ineligible for surgery because of their poor general health, concomitant anticoagulant or immunosuppressive therapies, or allergy to local anesthetics.2
Photodynamic therapy (PDT) with methyl aminolevulinate (MAL) is an innovative treatment modality that has been approved for the treatment of actinic keratosis,3 basal cell carcinoma,4 and Bowen’s disease.5 However, currently, there is insufficient evidence to support the routine use of topical PDT for SCC. Few studies have reported the therapeutic effect of MAL-PDT in the treatment of more advanced, invasive SCC. Calzavara et al2 reported the efficacy of MAL-PDT in the treatment of SCC according to the invasion depth. In this study, microinvasive SCC was defined as Clark level II (invasion into the papillary dermis) SCC, which MAL-PDT showed a higher efficacy for than for invasive (Clark level III and IV) and deeply invasive (Clark level V) SCC.
Many patients diagnosed with SCC are elderly and ineligible for surgery. Moreover, elderly patients usually do not want surgical treatment. Therefore, physicians face many complicated issues when choosing an appropriate treatment option for SCC patients with health-related issues, such as a bleeding tendency or cardiac problems, and those who refuse surgical treatment.
Erbium:yttrium-aluminum-garnet (Er:YAG) ablative fractional laser (AFL) ablates the epidermis and dermis without significant thermal injury, creating microscopic ablation zones in the portion of the skin that the laser is applied to. Our previous studies showed that AFL-primed MAL-PDT (AFL-PDT) offered a higher efficacy than conventional MAL-PDT in the treatment of many other diseases, such as actinic keratosis, actinic cheilitis, and Bowen’s disease.6-8 Therefore, we attempted to apply AFL-PDT for treating microinvasive SCC. We evaluated the efficacy of AFL-PDT and standard MAL-PDT in patients with microinvasive SCC for whom surgical excision would have been difficult because of bleeding abnormalities or cardiac problems. We recruited Korean patients with microinvasive SCC and compared the efficacy, recurrence rate, and cosmetic outcomes of AFL-PDT with those of standard MAL-PDT.
The study was designed as a 2-armed, randomized, single-blind, comparative trial. The trial protocol can be found in the Supplement. The study was approved by the institutional review board of the Dong-A University Medical Center and was conducted in accordance with the 1983 Declaration of Helsinki. All patients provided written informed consent before inclusion. Patients were not compensated for their participation.
This prospective study enrolled patients who had biopsy-proven SCC and who were treated at the Dong-A University Medical Center between January 2012 and December 2013. Before treatment, a 4-mm punch biopsy specimen was obtained from the most representative site, ie, the nodular or ulcerated area of the lesion, if present. Patients were randomly assigned to receive either AFL-PDT or MAL-PDT in sequence using a computer-generated program. We enrolled patients 18 years or older who had previously untreated microinvasive SCC, providing they satisfied both of the following conditions: (1) tumor invasion into the papillary dermis (Clark level II) according to a biopsy specimen and (2) difficulty in surgical excision because of health-related issues (bleeding tendency or cardiac problems). Exclusion criteria were as follows: pregnancy or lactation; active systemic infectious disease; other inflammatory, infectious, or neoplastic skin diseases in the treated area; allergy to MAL, other topical photosensitizers, or excipients of the cream; history of photosensitivity; use of immunosuppressive or photosensitizing drugs; participation in any other investigational study in the preceding 30 days; and history or indicators of poor compliance. Histological findings of acantholysis, desmoplasia, perineural or lymphovascular invasion, and echographic features of regional lymph node metastasis were the disease-specific exclusion criteria.
On the basis of the degree of cytological atypia, lesions were classified as moderately well differentiated (Broders’ score I-II) and poorly differentiated (Broders’ score III-IV).
All the microinvasive SCC lesions were photographed for baseline measurement. Subsequently, the eligible patients were randomized to treatment with a single AFL-PDT session or 2 MAL-PDT sessions with a 1-week interval between sessions using a computer-generated program. The investigators (S.H.C. and K.H.S.) who determined the clinical outcomes were not involved in the procedure to ensure that they remained blinded. The lesions were then cleansed with saline gauze, and a lidocaine-prilocaine 5% cream was applied to the treatment area for 30 minutes under occlusion. After removing the anesthetic cream, AFL was performed using a 2940-nm Er:YAG AFL (Sciton Inc) with 550- to 600-µm ablation depth, level 1 coagulation, 22% treatment density, and a single pulse. Immediately after the AFL, a 1-mm-thick layer of MAL 16% was applied to the lesion and to 5 mm of the surrounding healthy tissue. In the MAL-PDT group, the aforementioned Er:YAG AFL pretreatment procedures were omitted. Standard pretreatment such as curettage was not performed prior to PDT owing to a tendency to bleed. The area was covered with an occlusive dressing for 3 hours, after which the remaining cream was removed with saline gauze and the red fluorescence of porphyrins was visualized with Wood’s light. Each treatment area was then separately illuminated using red light-emitting diode lamps (Aktilite CL128; Galderma S.A.) with peak emission at 632 nm and a total light dose of 37 J/cm2. Areas scheduled to receive MAL-PDT received the second treatment 7 days later.
Patients visited our center for baseline measurement and for follow-up after 1 week, 3 months, 12 months, and 24 months. The treatment lesions were photographed at each visit.
The primary outcome measures were the lesion response at 3 and 24 months, and the recurrence rate 24 months after the last treatment. The secondary outcome measures were the investigator assessment of cosmetic outcome at 24 months, and the adverse events during treatment and at each follow up. A tertiary outcome measure was pain intensity during PDT illumination.
Efficacy was evaluated at 3, 12, and 24 months, and recurrence rates were evaluated at 24 months after the last treatment. Efficacy was assessed based on inspection, dermoscopy, photography, palpation, and histologic findings. Lesion responses were classified as either a complete response (complete disappearance of the lesion) or an incomplete response (incomplete disappearance). In all cases of complete response, the patients were reviewed at 12 and 24 months to check for recurrence. Posttherapy punch biopsies were performed when incomplete-response and clinical recurrence were suspected. An incomplete-response lesion at 3 months and recurrence lesions at 24 months were evaluated according to whether the lesion progressed to invasive SCC on biopsy.
The overall cosmetic outcome was assessed by each investigator for all lesions that achieved complete response at 24 months, and was graded using a 4-point scale: excellent (only slight occurrence of redness or change in pigmentation), good (moderate redness or change in pigmentation), fair (slight to moderate scarring, atrophy, or induration), or poor (extensive scarring, atrophy, or induration).
Safety assessments were performed at the end of the 3-hour cream application; after illumination during each treatment session; and at 1 week, 3, 12, and 24 months after the last treatment. During the illumination, patients were asked to evaluate pain intensity using an 11-point visual analog scale. Adverse events were reported spontaneously or responses were elicited by nonleading questions. If present, adverse effects were recorded at each visit, as were details about their severity, localization, duration, and the need for additional treatment. The severity of each adverse event was assessed as follows: mild (transient and easily tolerated), moderate (causing the patient discomfort and interrupting usual activities), or severe (causing considerable interference with usual activities and possibly incapacitating or life threatening). All adverse events associated with PDT were phototoxic reactions (eg, erythema, postinflammatory hyperpigmentation, edema, itching, oozing, and bleeding).
Based on 90% power of the 2-sided χ2 test, 50% difference in complete response rate at 24 months between the 2 groups (AFL-PDT group, 70% vs MAL-PDT group, 20%), and 5% level of significance, the number of sample size required is 18 per treatment group. Assuming the drop-out rate of 10%, the total number of sample size required is 40 (20 per treatment group). Numeric variables were summarized as the mean SD, and categorical variables were summarized as the counts and relative frequencies. Complete response rates and cosmetic outcomes were compared between the treatment groups by using the χ2 test. Furthermore, 95% CIs were estimated using binomial distribution. Visual analog scale pain scores were compared using the independent t test. Adverse events were summarized with respect to the treatment method. All data were analyzed using SPSS statistical software (version 17.0, SPSS Inc). A P value of <.05 was deemed statistically significant.
Forty-five Korean patients were enrolled in this study. The patients were randomized to treatment with AFL-PDT (21 patients) or MAL-PDT (24 patients). Five subjects dropped out prematurely: 1 dropped out because of health-related issues and 4 were lost to follow-up. The per-protocol (PP) population comprised 40 patients, 19 of whom were treated with AFL-PDT and 21 of whom were treated with MAL-PDT. A flowchart of the patient selection process is presented in Figure 1. The baseline characteristics of the 2 groups were similar. Patient and lesion characteristics are summarized in Table 1. Unless otherwise specified, results are shown for the intent-to-treat (ITT) population.
Three months after the last treatment, the complete response rate was significantly higher for AFL-PDT (84.2%; 95% CI, 67.4%-99.9%) than for MAL-PDT (52.4%; 95% CI, 30.5%-74.3%) in the PP population (P = .03). In the ITT population, the efficacy after 3 months was also significantly higher for AFL-PDT (76.2%; 95% CI, 57.5%-94.9%) than for MAL-PDT (45.8%; 95% CI, 25.5%-66.2%; P = .04). These differences in efficacy remained significant at the 24-month follow-up for both the PP and ITT populations (Table 2). Clinical photographs and histological findings of the AFL-PDT group at baseline measurement, 1 week, 3 months, 12 months, and 24 months are shown in Figure 2.
Among the patients who failed to show a complete response for AFL-PDT at 3 months, no patients showed progression to invasive SCC according to their biopsy specimens. In contrast, 1 patient of 10 (10%) showed progression to invasive SCC after MAL-PDT (an incomplete response at 3 months in the MAL-PDT group). Among the patients with recurrences at 24 months, no patient progressed to invasive SCC in the AFL-PDT group. However, among those with recurrences at 24 months, 2 of 8 (25%) patients in the MAL-PDT group progressed to invasive SCC. Patients who showed incomplete response at 3 months and recurrence at 12 and 24 months in both the AFL-PDT and MAL-PDT groups were treated with surgery or radiotherapy.
Recurrence rates at 12 months were significantly lower with AFL-PDT (12.5%; 95% CI, 0.1%-29.2%) than with MAL-PDT (63.6%; 95% CI, 33.8%-93.5%; P = .006). These differences in recurrence rate between AFL-PDT (18.8%; 95% CI, 0.1%-38.5%) and MAL-PDT (72.7%; 95% CI, 45.1%-99.9%) remained significant at the 24-month follow-up (P = .005).
In the PP population, we evaluated cosmetic outcomes among the patients who achieved a complete response at 24 months. Outcomes were excellent or good in 10 of 13 patients (77%) in the the AFL-PDT group and 2 of 3 (67%) patients in the MAL-PDT group. Cosmetic outcomes were fair or poor in 3 of 13 (23%) patients in the AFL-PDT and 1 of 3 (33%) patients in the MAL-PDT group. However, we could not detect any statistical significance because of the small sample size.
None of the patients complained of pain or discomfort during AFL pretreatment in the AFL-PDT group. All patients demonstrated local adverse reactions that were resolved within 7 days after the PDT treatment without any complications. The most common local adverse events were erythema, crusting, hyperpigmentation, pruritus, and burning sensations. Their occurrence was slightly higher in the AFL-PDT group than in the MAL-PDT group, but the differences were not statistically significant. Patients’ local adverse events are summarized in Table 3. Most adverse events were mild to moderate and tolerable. No systemic adverse events were observed. All patients experienced mild to moderate pain during PDT illumination. After illumination had ceased, pain management included the use of a fan or cooling sprays, and the pain intensity immediately lessened and resolved over the following few hours. Visual analog scale scores (11-point scale) during illumination were similar for both the AFL-PDT (6.0; SD, 1.7) and MAL-PDT groups (5.7; SD, 1.7) (P = .59).
To the best of our knowledge, the efficacy of AFL-PDT for microinvasive SCC has not been reported previously. In the present study, we found that AFL-PDT is more efficacious than conventional MAL-PDT for treating microinvasive SCC lesions. AFL-PDT provided a significantly higher complete response rate at 3 months (84.2%) than conventional MAL-PDT (52.4%) and these differences remained significant at the 24-month follow-up. The high long-term efficacy of AFL-PDT resulted from the lower 24-month recurrence rate in the AFL-PDT group compared with the MAL-PDT group. The combined excellent and/or good cosmetic outcome rates were similar for AFL-PDT and MAL-PDT. However, we could not identify any statistical significance owing to the small sample size. Compared to other treatment options, MAL-PDT produces better cosmetic outcomes and improved satisfaction.5 Moreover, use of the Er:YAG fractional laser minimizes the coagulation zone per pass, resulting in faster wound healing.9-12 The AFL-PDT and MAL-PDT approaches were both safe and well tolerated, as demonstrated by similar visual analog scale pain scores and no significant differences. None of the patients discontinued the study because of adverse events, which included erythema, crusting, hyperpigmentation, burning sensations, pruritus, edema, and bullae.
The major rate-limiting step for drug absorption is passage through the stratum corneum. The AFL treatments evaporate tissue and leave a matrix of microscopic ablation zones consisting of vertical ablated channels surrounded by a rim of coagulated tissue.13 Therapy with Er:YAG AFL can also ablate the stratum corneum in a precisely tuned manner without producing excessive thermal injury. Because Er:YAG AFL accomplishes the resurfacing of 5% to 20% of the skin at 1 time and does not create injuries along the entire thickness of the epidermis, healing times are minimized.14,15 Recent studies have demonstrated that AFL therapy facilitates the delivery and uptake of topical MAL deep into the skin, enhancing porphyrin synthesis and photodynamic activation.16,17 The use of AFL-PDT provides the additional benefit in that AFL alone also shows therapeutic effect. In our study, aggressive debulking procedures like curettage were not performed owing to a tendency to bleed. This may have resulted in the disappointing efficacy of MAL-PDT. However, AFL-PDT resulted in sufficient efficacy. Although higher efficacy of AFL-PDT is mainly owing to increased MAL absorption after AFL pretreatment, ablation of tumors with AFL may have contributed to these results. Owing to the small sample size, we did not compare the efficacy of AFL alone in microinvasive SCC.
The use of AFL-PDT was demonstrated to have superior efficacy for many premalignant lesions (AK, actinic cheilitis, and Bowen’s disease).6-8,12 However, its efficacy for invasive skin cancer was unknown. Haak et al18 demonstrated that AFL-PDT did not show significantly higher long-term efficacy compared with conventional PDT in treating BCC. However, AFL-PDT may offer an alternative treatment option for some invasive skin cancers. Our previous study demonstrated that AFL-PDT shows efficacy in thin nodular BCC.19 Moreover, we also demonstrated the efficacy of AFL-PDT in microinvasive SCC in this study.
In addition to higher treatment efficacy and lower recurrence rate, AFL-PDT had another advantage. We observed that the lesions that failed to achieve complete response after AFL-PDT did not progress to invasive SCC at 3 and 24 months. In contrast, progression to invasive SCC was observed in some patients after conventional MAL-PDT. Recently, some authors have reported rapid development of SCC after photodynamic therapy.20,21 PDT may lead to accelerated tumor growth because of its immunosuppressive effect. In particular, PDT has been found to cause an early and sustained reduction in epidermal Langerhans cells, which play an important role in antigen presentation.22 In the present study, we observed progression of lesions after MAL-PDT. However, after AFL-PDT no patient showed progression to invasive SCC. Consequently, AFL-PDT leaves few remnant SCC lesions because of a deep treatment area. As a result, the possibility that remnant tumor cells will progress to invasive SCC in an immunosuppressive environment is very low.
Calzavara-Pintonet al2 suggested some prognostic factors for treating SCC with PDT. In this study, SCC lesions were classified according to microscopic depth of invasion, cytologic atypia, and diameter, all of which influence the efficacy of PDT. In particular, PDT achieved significantly higher efficacy for microinvasive SCC (57.5%, complete response at 24 months) than for invasive SCC (25.8%, complete response at 24 months). Generally, PDT is contraindicated for SCC because of its low efficacy and high recurrence rate. However, microinvasive SCC should be differentiated from invasive SCC, because dermal invasion is minimal and limited to the papillary dermis. Consequently, the treatment strategy for microinvasive SCC should be differentiated from that for invasive SCC.
In this study, we achieved higher efficacy for microinvasive SCC treatment in the AFL-PDT group than in the previous study using conventional MAL-PDT. We suggest that MAL-PDT had insufficient efficacy because of its low complete response rate and high recurrence rate. Although AFL-PDT showed higher efficacy than MAL-PDT, the efficacy was less compared with surgical treatment. To overcome the lower efficacy of AFL-PDT, additional repetitive treatment could be performed. In this study, we performed only one session of AFL-PDT. If another session of AFL-PDT is performed, higher efficacy could be achieved than in the current study.
Although AFL-PDT showed good efficacy in microinvasive SCC, surgical excision is the treatment of choice for microinvasive as well as invasive SCC. Generally, PDT is contraindicated for SCC owing to lower efficacy; AFL-PDT is commonly used off-label in SCC. However, many elderly patients do not wish to have surgical treatment or have difficulty with surgery because of health problems (bleeding tendency or cardiac problems). Therefore, AFL-PDT should be considered as an alternative option for microinvasive SCC in inoperable patients.
However, this study has some limitations. In this study, SCC were classified according to Clark levels and microinvasive SCCs were recorded with a Broders' score because microinvasive SCC is not a widely accepted entity. Consequently, standardized methods of measuring thickness have not been reported for these tumors. In the present study, we judged tumor depth based on biopsy specimens. However, the tumor depth measured in a biopsy specimen is not representative of the entire lesion and this may present some bias. Second, the patients may have been able to differentiate between the 2 treatments because of the characteristics of the Er:YAG pretreatment. Third, the results are limited by the small sample size. Fourth, although there was no statistically significant difference between both groups, sex distribution was uneven and may have influenced the results. Therefore, a multicenter study with a larger sample size and various ethnic groups is recommended to confirm our results. Finally, we did not compare the efficacy of AFL-PDT with that of AFL alone in microinvasive SCC.
This treatment may be offered if the patient is not a candidate for surgical treatment, which remains the treatment of choice for microinvasive SCC. Although our approach was not as successful as surgical treatment, we suggest that AFL-PDT could be a good alternative treatment option for microinvasive SCC considering that only 1 session of AFL-PDT was performed. Most patients who were diagnosed with SCC were elderly. Therefore, we recommend deciding the treatment modality according to the invasion depth rather than unconditionally choosing surgery because many elderly patients have health-related issues and are ineligible for surgery. For such patients, AFL-PDT could be a good alternative in cases of superficial SCC (microinvasive SCC and SCC in situ).
Corresponding Author: Ki-Hoon Song, MD, PhD, Department of Dermatology, College of Medicine, Dong-A University, Dong dae sin-dong, Seo-gu, Busan, 602-715, Republic of Korea (firstname.lastname@example.org).
Accepted for Publication: September 28, 2016.
Published Online: February 15, 2017. doi:10.1001/jamadermatol.2016.4463
Author Contributions: Drs Choi and Song had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Choi, Song.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Choi, Song.
Critical revision of the manuscript for important intellectual content: Kim, Song.
Statistical analysis: Choi, Song.
Obtained funding: Song.
Administrative, technical, or material support: Song.
Study supervision: Song.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by research funds from Dong-A University.
Role of the Funder/Sponsor: Dong-A University had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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