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Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Background

Photodynamic therapy (PDT) is a well-documented treatment for actinic keratosis (AK), but achieves inferior efficacy in organ transplant recipients (OTRs), particularly in acral regions. Ablative fractional laser (AFXL) intensifies the PDT response and may improve the efficacy of AK clearance when used as monotherapy.

Objectives

To compare the efficacy of a single treatment with AFXL-assisted PDT vs. AFXL alone for difficult-to-treat AKs and wart-like lesions (WLLs) in OTRs.

Methods

Ten OTRs were included with a total of 680 AKs (severity grade I–III) and 409 WLLs on the dorsal hands. Both hands were initially treated with targeted fractional ablation of thick keratotic lesions followed by AFXL field treatment. Treatment regions were then randomized to (i) PDT (AFXL-PDT) or (ii) no further treatment (AFXL). The primary end point was complete response (CR) at 4 months after treatment; secondary end points were improvement of AK severity grade, overall patient assessment of efficacy and tolerability of treatments.

Results

CR of AKs was significantly higher for AFXL-PDT (73%) compared with AFXL alone (31%) (= 0·002). AFXL-PDT improved 82% of AKs to lower lesion grades compared with 52% after AFXL alone (= 0·008). For WLLs, the rate of CR was 37% for AFXL-PDT compared with 14% for AFXL (= 0·02). Overall assessment showed a preference for AFXL-PDT compared with AFXL (AFXL-PDT,= 8; AFXL,= 0; equal, = 2). Mild pigment changes were observed in four patients (AFXL-PDT,= 3; AFXL,= 1). No scarring was observed.

Conclusions

AFXL-PDT is more effective than AFXL in the treatment of acral AKs and WLLs in OTRs.

Organ transplant recipients (OTRs) are at increased risk of developing malignancies, in particular cutaneous squamous cell carcinomas (SCCs), compared with the general population, because of the obligatory immunosuppression following solid organ transplantation. The relative risk of SCC is estimated to be 65–250-fold in OTRs compared with the rest of the population,[1, 2] increasing with time after transplantation and depending on the type of organ transplant. Thus, a recent Nordic population-based study found a 300-fold increased risk of SCC in heart and/or lung recipients and a 200-fold increased risk among kidney recipients at 20 years post-transplantation.[3] SCCs outnumbered all other cancer types and the standardized mortality ratio for SCCs was 50. It is expected that cancer diseases will become the leading cause of death in OTRs in the coming decades.[3, 4]

Actinic keratosis (AK) is a premalignant condition associated with the development of SCC. OTRs often develop multiple AKs in chronically sun-exposed areas, representing skin areas with field cancerization.[5] Treatment options include targeted therapy such as cryotherapy, excisional surgery and curettage, as well as field-directed strategies with photodynamic therapy (PDT), 5-fluorouracil and diclofenac.[5] Recent European guidelines recommend PDT for the treatment of field cancerization.[6, 7] PDT utilizes aminolaevulinic acid or methyl aminolaevulinate (MAL), both of which are precursors of the endogenous photosensitizer protoporphyrin IX (PpIX), which accumulates in dysplastic epidermal cells. After illumination with light, PpIX is photoactivated and produces cytotoxic reactive oxygen species. PDT is an effective treatment of AK in OTRs on the face and scalp, demonstrating complete response (CR) rates of 56–77%, whereas lower response rates (40%) are observed in acral lesions.[8-10] The variation in efficacy may be due to more hyperkeratotic lesions, which can hamper the penetration of MAL, and PpIX formation within the skin lesions,[11] occurring in acral than face and scalp regions.

Ablative lasers, as well as their fractional counterparts, are being used for the treatment of AKs,[12-14] but the true efficacy of ablative fractional laser (AFXL) alone has so far not been studied systematically for AKs. AFXL has been demonstrated to facilitate the uptake of topically applied photosensitizers with a uniform and intensified distribution of MAL-induced PpIX.[15, 16] In a recent randomized clinical trial, AFXL combined with MAL-PDT was more effective than conventional PDT for AK clearance in field-cancerized skin in immunocompetent patients.[17]

The purpose of this study was to evaluate the efficacy of AFXL-assisted PDT compared with AFXL alone in a randomized half-side comparative clinical trial for treatment of field-cancerized skin of the dorsal hands in immunosuppressed and difficult-to-treat OTRs.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Patients

OTRs were recruited from the Department of Dermatology, Oslo University Hospital, and identified through a quality assurance register for OTRs (Medinsight®; Institute for Medical Informatics, Oslo University Hospital, Oslo, Norway). Inclusion criteria were OTRs with symmetric and more than five AKs on each dorsal hand, age above 18 years, stable graft function and signed written informed consent. Exclusion criteria were pregnancy or lactation, infiltrating tumour or PDT treatment of the dorsal hands within the past 3 months, allergy to constituents of the MAL cream, porphyria and tendency to produce hypertrophic scars or keloids. The register was approved by the local data protection official and the study was approved by the regional ethical committee and conducted according to the Declaration of Helsinki. The study was registered on ClinicalTrials.gov (identifier: REK2011/1959).

Study protocol

Patients were evaluated on the day of treatment and 4 months after the procedure. Treatment areas included the dorsal hands from the wrist to the metacarpal joints. All lesions within the treatment areas were mapped on a template, numbered and categorized as AKs or wart-like lesions (WLLs). AKs were erythematous and keratotic, whereas WLLs were pale, broad based and nonscaly. The severity grading used for AK was according to Olsen et al.[18] (mild 1: slightly palpable AK, more easily felt than seen; moderate 2: moderately thick AK, easily felt; and severe 3: very thick or obvious AK) and also applied to WLLs. Nonlesional skin was categorized clinically as atrophic or nonatrophic. Photos were captured at baseline and at follow-up visits for documentation.

Pain during AFXL-PDT was registered on a visual analogue scale (VAS). All patients were contacted by short message service 1 week and 1 month after treatment to give them the opportunity to report adverse events. Post-treatment pigment changes and scarring were registered at the 4-month follow-up.

Treatment procedures

A fractional ablative CO2 laser was used at 10 600 nm, 30 W and 0·12-mm spot size (eCO2; Lutronic, Ilsan Techno Town, Korea). AFXL treatment was performed in two passes; firstly a lesion-targeted treatment of AKs and WLLs grades 2 and 3 on both hands, followed by a second pass given as a field treatment of the entire dorsal hand.

First-pass targeted laser settings were 160 mJ per pulse, 6·25-ms pulse duration and 5·3% coverage (nonatrophic skin) and 140 mJ per pulse, 5·65-ms pulse duration and 5·2% coverage (atrophic skin). The second field-directed pass settings were 60 mJ per pulse, 2·06-ms pulse duration and 5·2% coverage (nonatrophic skin) and 40 mJ per pulse, 1·32-ms pulse duration and 4·3% coverage (atrophic skin).

After laser exposure of both hands, MAL cream was applied to one dorsum as per allocation (Metvix® cream 16%; Galderma, Biot, France), occluded for 3 h under a plastic film and illuminated with red light-emitting diode (LED) light at 632 nm at a dosage of 37 J cm−2 (Aktilite®; Galderma, Oslo, Norway). Local anaesthesia with bupivacaine 5 mg mL−1 (Marcain-Adrenalin®; AstraZeneca, London, U.K.) was given on patient request. All patients received prophylactic dicloxacillin (Diclocil®; Bristol-Myers Squibb, New York City, NY, U.S.A.), 500 mg three times a day starting on the day of treatment and continuing for an additional 4 days.

Outcome measures

Blinded clinical assessments were performed 4 months after treatment. The primary end point was the proportion of lesions with CR for each patient. The secondary end points were the proportion of lesions that improved in AK severity grade, overall patient assessment of efficacy from interventions, and tolerability. Patient assessment of efficacy reflected the patients' judgement of which dorsal hand had responded best to treatment. Evaluation of pain during treatment was given on a VAS scale, 0 being no pain and 10 the worst pain ever experienced. Long-term adverse events were scarring and pigment changes, and were scored as none, mild, moderate or severe. Patients' preference and long-term adverse events were supported by pretreatment photographs.

Random allocation and statistical analysis

The randomization procedure was performed by drawing sealed, opaque envelopes containing allocation to PDT. Randomization was performed after AFXL treatment of both hands and allocations were kept concealed from the assessors.

CR and improvement of AK severity grade were calculated for all AKs and WLLs within each patient and compared by the Wilcoxon signed-rank test. This analysis was also performed for AKs and WLLs stratified by grade. In addition, treatment response was assessed as odds ratios (ORs) with 95% confidence intervals (CIs) using a logistic regression model with generalized estimating equations (GEEs; robust estimator and exchangeable working correlation) adjusted for AK grade (categorical with grade 1 as the reference). A reduction in AK grade from before to after treatment was classified as improved. We estimated the treatment effect on improvement of AK severity grade (improved/not improved) as ORs with 95% CIs using a logistic regression model with GEEs with adjustment for AK grade as described above. We tested for interaction between treatment and AK grade in the logistic regression models for CR and improvement of AK severity grade. These results are not shown, as no interaction effects were found. The statistical analyses were performed using GraphPad Prism version 5.0 (GraphPad Software, La Jolla, CA, U.S.A.) and SPSS version 20 (IBM, Armonk, NY, U.S.A.) for the logistic GEE analysis. All P-values were two-sided and P-values < 0·05 were considered significant.

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Patients

Ten patients (five men and five women) (Table 1) with a total of 680 AKs and 409 WLLs were included in the study. Patients were Fitzpatrick skin type II (= 5) and III (= 5); mean age at inclusion was 64 years (range 55–74 years). Eight patients had had kidney transplants, one a liver transplant and one a heart transplant. The median time since transplantation was 30 years (range 17–42 years) and the patients had a total of 19 previous SCCs. Five patients were treated with a double immunosuppressive regimen and five patients with a triple regimen. A mammalian target of rapamycin (mTOR) inhibitor (everolimus) was included in the regimen for six patients (Table 1). The numbers of AKs and WLLs were comparable between treatment areas at baseline (Table 2).

Table 1. Description of study patients
PatientAge (years)SexOrganFitzpatrick skin typeImmunosuppressionYears since transplantRegimenaNo. of previous SCCs
  1. SCC, squamous cell carcinoma; Pred, prednisolone; Aza, azathioprine; MMF, mycophenolate mofetil; CS, ciclosporin/tacrolimus; mTOR, mammalian target of rapamycin inhibitor (everolimus). aRegimen 1, 160 mJ (6·25 ms) to hyperkeratotic lesions, 60 mJ (2·06 ms) field treatment, density 5·3%/5·2%; regimen 2, 140 mJ (5·65 ms) to hyperkeratotic lesions, 40 mJ (1·32 ms) field treatment, density 5·0%/4·3%.

161FemaleKidneyIIPred/Aza3820
272MaleLiverIIPred/MMF/mTOR1721
364FemaleKidneyIIPred/mTOR3220
471MaleKidneyIIIPred/MMF4221
557MaleKidneyIIPred/MMF/mTOR3711
667MaleKidneyIIIPred/MMF/CS2310
774MaleKidneyIIIPred/CS/mTOR2012
856FemaleHeartIIPred/MMF/mTOR2621
955FemaleKidneyIIIPred/mTOR4213
1064FemaleKidneyIIPred/CS23110
Table 2. Actinic keratoses (AKs) and wart-like lesions (WLLs) at baseline and complete response (CR) at 4 months after a single treatment with ablative fractional laser and photodynamic therapy (AFXL-PDT) vs. AFXL alone
Grade of lesionBaseline, number of lesionsCR at 4-month follow-up (%), median (min–max)P-value
AFXL-PDTAFXLAFXL-PDTAFXL
All AKs33534573 (25–94)31 (8–57)0·002
AKs 117317980 (29–100)37 (0–68)0·02
AKs 212713653 (0–100)7 (0–31)0·009
AKs 335304 (0–89)0 (0–50)0·17
All WLLs21119837 (0–91)14 (0–43)0·02
WLLs 11279831 (0–100)22 (0–33)0·06
WLLs 2749214 (0–50)0 (0–43)0·04
WLLs 31080 (0–20)0 (0–0) 

Reduction of actinic keratoses and wart-like lesions

For all AKs, AFXL-PDT resulted in a significantly higher median CR of 73% compared with 31% with AFXL (Fig. 1, Table 2, = 0·002). Stratifying by AK grade, AFXL-PDT was significantly more effective than AFXL alone for grade 1 (80% vs. 37%, = 0·02) and grade 2 AKs (53% vs. 7%, = 0·009), while no significant difference was found for grade 3 AKs (4% vs. 0%, = 0·17). Correspondingly, the odds of achieving CR were significantly higher (< 0·001) from AFXL-PDT treatment compared with AFXL treatment (OR 4·2, 95% CI 1·96–8·98; after adjustment for AK grade OR 4·65, 95% CI 2·21–9·77). There was a significant effect of AK grade in this model (< 0·001): ORs were 0·34 (95% CI 0·23–0·48) for AK grade 2 vs. 1; and 0·21 (95% CI 0·11–0·39) for AK grade 3 vs. 1.

image

Figure 1. Hands of a kidney transplant recipient before treatment (a, b) and 4 months after ablative fractional laser (c) and ablative fractional laser-assisted photodynamic therapy (d).

Download figure to PowerPoint

Improvement of AKs to a lower severity grade was achieved in 82% of AKs from AFXL-PDT compared with 52% from AFXL (Table 3, medians, = 0·008). Correspondingly, the OR for AKs being reduced to a lower severity grade was 3·32 (95% CI 1·66–6·65, = 0·001) in favour of AFXL-PDT compared with AFXL treatment. This estimate was similar after adjustment for AK grade (OR 3·36, 95% CI 1·62–6·99). There were fewer new AKs in the AFXL-PDT-treated areas (= 2) compared with the AFXL-treated areas (= 7).

Table 3. Overall response of actinic keratoses (AKs) and wart-like lesions (WLLs) at 4 months after a single treatment with ablative fractional laser and photodynamic therapy (AFXL-PDT) vs. AFXL alone
 4-month follow-upP-value
Number of lesionsTreatment response (%), median (min–max)
AFXL-PDTAFXLAFXL-PDTAFXL
  1. a

    Improved, improved to a lower lesion grade; unchanged, unchanged lesion grade; worsened, developed into a higher lesion grade.

AKs
 Improveda25515682 (56–100)52 (16–64)0·008
 Unchanged6016715 (0–29)47 (35–76)
 Worsened20223 (0–15)4 (0–8)
WLLs
 Improved1116656 (20–91)30 (13–71)0·02
 Unchanged8211640 (2–57)22 (0–33)
 Worsened18163 (0–33)8 (0–20)

WLLs attained lower CR than AKs after both AFXL-PDT and AFXL, with a median CR of 37% for AFXL-PDT and 14% for AFXL alone (Table 2, = 0·02). The rate of improvement of WLLs to a lower severity grade was 56% after AFXL-PDT treatment compared with 30% after AFXL alone (Table 3, medians, = 0·02).

At the 4-month follow-up, patients evaluated the overall treatment efficacy; eight favoured AFXL-PDT, none favoured AFXL alone and two regarded the treatments as equal.

Tolerability

Infiltration anaesthesia was given to seven patients; five patients during AFXL treatment and two during LED illumination. Three patients received no local anaesthesia. The median VAS pain score during AFXL treatment was 1 (range 0–7) and during illumination, 4·5 (range 1–10).

Five patients responded to the short message service at 1 week, three patients submitting pictures that showed intense inflammation and purpura. Three patients reported erythema, oedema and pain at 1 week after treatments. No patients responded to our request to report additional adverse events after 1 month.

Clinical evaluation from pre- and post-treatment photographs showed no scarring in treated areas. Mild hypopigmentation was noted in four patients (AFXL-PDT = 3, AFXL = 1).

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

In this study, we found that a single treatment with AFXL-PDT is highly effective for difficult-to-treat AKs and WLLs in immunosuppressed OTRs. Furthermore, both AFXL-PDT and AFXL reduced the numbers of acral AKs and WLLs; however, AFXL-PDT was significantly more effective than AFXL alone for clearing both AKs and WLLs.

PDT with MAL has been recommended as an effective treatment for AKs in OTRs with field-cancerized skin.[6, 7] Studies have reported CR rates of 56–77% for AKs on the face and scalp at 3–4 months after one or two treatments.[8-10] but significantly lower CR rates for acral AKs.[8, 9] Dragieva et al.[8] found CR of the entire treatment area in two of nine OTRs with AKs on the back of their hands 12 weeks after one or two MAL-PDT treatments. In a second study, Piaserico et al.[9] reported a complete lesion response in 40% of acral AKs, whereas 72% of AKs located on the face and scalp cleared completely at 12 weeks following two PDT sessions. We found that AFXL-PDT for these difficult-to-treat AKs resulted in 73% CR from just one treatment session, which corresponds to response rates for AKs located in the face and scalp regions. These findings suggest that AFXL-PDT treatment for acral AKs may be as effective as conventional PDT for AKs on the face and scalp of OTRs.

No previous studies have evaluated the efficacy of AFXL alone for the treatment of AKs, whereas the effect of ablative laser resurfacing, such as CO2 laser (10 600 nm) and erbium-doped yttrium aluminium garnet laser (erbium:YAG; 2940 nm) has been investigated for AK treatment in the scalp region in immunocompetent patients.[12, 13] Hantash et al.[12] found a CR rate of 92% at 3 months following CO2 laser resurfacing of AKs in the scalp region. Studies on erbium:YAG resurfacing have reported similar CR rates (79–89%) evaluated 3–6 months after treatment.[13] So far, no studies have evaluated the effect of ablative resurfacing of AKs in OTRs. Fractional nonablative laser treatment for multiple AKs has been studied in immunocompetent patients, using a 1550-nm erbium-glass fractionated laser in 10 patients receiving between five and 10 treatments at 4-week intervals.[14] The patients used tretinoin 0·025% between treatments, and there was an overall reduction of 54% in the number of AKs using a four-point physician global assessment scale. Both laser treatment and use of tretinoin may have contributed to this result. We found a 31% CR rate in AK following AFXL alone at the 4-month follow-up. This relatively low response rate is most likely due to the acral location of AKs, the fact that patients were immunosuppressed, and also the concept of fractional resurfacing, in which fractions of the skin are treated, thus leaving areas of untreated epidermal dysplasia, which may increase the risk of treatment failure from nonlaser-exposed skin areas.

Hyperkeratosis is considered one of the main reasons for reduced efficacy of PDT in acral lesions.[11, 19] Hyperkeratosis may prevent uniform absorption of the photosensitizing agent, resulting in insufficient PpIX production and thus leading to inferior treatment response. Impairment because of hyperkeratosis may be overcome by pretreating the skin with keratolytics or by mechanically disrupting the skin barrier in order to increase penetration of the photosensitizer.[20] The use of AFXL in combination with PDT has been established in animal studies, which documented improved bioavailability after pretreating the skin with ablative fractional CO2 laser.[15] This was confirmed in a human study by Togsverd-Bo et al.,[17] who found a superior treatment outcome using AFXL-assisted PDT compared with conventional PDT for AKs in immunocompetent patients. In OTRs, microneedling was used in a small study of 12 patients with 59 AKs, showing a CR after three PDT treatments of 83% at the 9-month follow-up.[21] In our study, we used AFXL-PDT for difficult-to-treat acral AKs in OTRs to obtain a CR of 73%, with an OR for CR of 4·65 compared with AFXL after only one treatment. The results are favourable compared with previous studies of OTRs,[8, 9] and our data are comparable with results obtained in the nontransplant population after one conventional PDT using MAL independent of localization.[6]

A disadvantage of PDT, and AFXL-PDT in particular, is pain during illumination and inflammatory reactions post-treatment. During treatment, seven of 10 patients requested local anaesthesia, which resulted in VAS scores comparable with illumination during conventional PDT,[22] but lower than those reported by Togsverd-Bo et al.[17] Both these studies treated mainly head/scalp lesions without local anaesthesia. Pain and a pronounced inflammatory reaction will probably necessitate some adjustment of the treatment regimen. AFXL-assisted daylight PDT may be such an option, as daylight PDT is recommended to reduce pain during treatment.[23] However, daylight PDT has not been shown to reduce the inflammatory reaction after PDT.[24]

Few patients and a relatively short follow-up are limitations of this study. However, long-term follow-up periods without additional treatments are hampered in these difficult-to-treat patients, who require cyclic treatments in order to prevent tumour development (Fig. 1c). There were lesions that were hard to categorize as either AK or WLL, but the superior treatment response in AKs indicates that dysplastic lesions have been correctly categorized.

We found that AFXL-PDT is more effective than AFXL alone in the treatment of acral AKs and WLLs in OTRs. Following only one treatment with AFXL-PDT for acral AKs, we achieved comparable efficacy rates with those observed in nontransplant patients treated once with PDT.

References

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References