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Where Do Fractional Lasers Fit in Keratinocyte Carcinoma Prevention? A Clinician-Facing Framework

  † These authors contributed equally to this work and share first authorship.

Submitted:

23 October 2026

Posted:

26 October 2026

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Abstract
Background: Fractional lasers have emerging evidence for actinic keratosis (AK) treatment and keratinocyte carcinoma (KC) prevention. The practical guidance for their clinical use remains less clear. Existing studies vary in laser type, treatment settings, PDT protocol, patient population, and follow-up, making it difficult to translate the literature into a usable clinical approach. Objective: To develop a clinician-facing framework for selecting patients and sequencing fractional lasers with field-directed therapy for AKs and field cancerization. Methods: We reviewed 48 manuscripts on fractional laser monotherapy, ablative fractional laser-assisted photodynamic therapy (AFXL-PDT), laser-assisted drug delivery, mechanistic studies, and high-risk populations. Evidence was mapped into a stepwise clinical algorithm. Results: The proposed algorithm first excludes patients with isolated AKs, suspicious lesions requiring biopsy, active infection, poor wound healing risk, or inability to tolerate recovery. Patients with multiple or recurrent AKs, diffuse photodamage, prior KC, or high procedural burden may be considered for fractional laser-based field therapy. AFXL-PDT is favored for thicker lesions, extensive field disease, or immunosuppressed patients, while non-ablative fractional lasers may fit selected patients who prioritize tolerability, cosmetic improvement, and limited downtime. Illumination and incubation choices should reflect the tradeoff between clearance, pain, convenience, and durability. Follow-up at 6–9 months is suggested because field control is not indefinite. Conclusion: Fractional lasers are best viewed as field-directed or adjunctive tools, not replacements for biopsy or standard oncologic care.
Keywords: 
fractional laser
;  
keratinocyte carcinoma
;  
actinic keratosis
;  
photodynamic therapy
;  
chemoprevention
Subject: 
Medicine and Pharmacology  -   Dermatology

Introduction

Actinic keratosis (AK) and keratinocyte carcinoma (KC), which comprises basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), impose an enormous and growing burden on patients and health systems. In the United States, 20% of people will develop a KC by age 70, and KC ranks among the five most costly cancers for Medicare [1]. AK, the most common precancerous keratinocyte lesion, arises on chronically sun-exposed skin in fair-skinned individuals; many patients develop new lesions each year.
AKs and KCs arise within broader areas of chronically UV-damaged skin that contain many of the same molecular alterations as the lesions themselves, a phenomenon known as field cancerization. Chronic UV exposure promotes mutations in tumor suppressor genes such as TP53, creating a field of genetically altered keratinocytes from which AKs and KCs can develop. Within this damaged field, subclinical (non-visible) AKs occur approximately ten times more frequently than clinically visible lesions, and the area of genetic damage can extend several centimeters around visible lesions [2]. This provides the mechanistic basis for the continued appearance of new lesions after individual lesions are treated.
Because the entire field carries carcinogenic potential, treating individual AKs or KCs as they arise may be insufficient for patients with significant UV damage. New lesions can continue to develop from the damaged skin surrounding treated lesions. This cycle results in repeated clinic visits, morbidity from repeated procedures, and substantial cost, especially for patients in high-risk groups such as organ transplant recipients and older fair-skinned patients with significant photodamage. Field-directed therapies, such as topical agents and photodynamic therapy (PDT), have emerged in response to this concern and are now favored over lesion-directed therapy for selected patients.
Despite the growing use of field-directed treatment, there is no consistent framework for deciding when and how to intervene in a cancerized field before new AKs or KCs develop. This is particularly true for fractional lasers, which have been shown to have a preventive effect, but data on practical application and implementation in clinical practice are lacking.

Background

Prior reviews have covered biologic mechanisms, prevention evidence, and lasers as treatment for established KCs. Wenande et al. highlight current evidence that ablative fractional lasers decrease the development of AK and KC in controlled trials of photodamaged patients [1]. The review also outlines the mechanistic rationale for fractional lasers, including the removal of damaged epidermis, activation of insulin-like growth factor-1 (IGF-1) signaling, reduction of fibroblast senescence, and induction of immunomodulatory effects [1]. Complementing this mechanistic and prevention focus, a 2024 review evaluated lasers as a treatment modality for established KC, focusing on efficacy and comparison with conventional surgical management [3].
Together, the current literature provides a biologic rationale for how fractional lasers might prevent AK and KC formation, as well as outcome data for lasers in established KC. However, there is limited literature detailing the practical application and implementation of fractional lasers for AK/KC prevention and treatment, including patient selection, indications for ablative versus non-ablative lasers, indications for combination therapy, and when lasers can or cannot replace standard care.
This review is intended to address that gap. We aim to synthesize the current data and provide a clinical framework that will allow dermatologists to implement fractional lasers in the management of cancerized fields.

Clinical Framework

Patient Selection: Who will benefit from lasers beyond standard field therapy?
Fractional lasers are most defensible as a field-directed intervention in patients with diffuse actinic damage rather than isolated lesions. Several studies have evaluated laser resurfacing in patients with extensive AK burden, prior KC, or severe photodamage, supporting the idea that laser-based approaches may be most appropriate when the clinical problem is a persistently active cancerized field rather than a small number of discrete AKs [4,5]. In a retrospective series of 24 patients with widespread facial AKs, defined as more than 30 lesions, full-face CO2 and/or erbium:YAG (Er:YAG) resurfacing produced an overall 94% reduction in AKs, with 87% of patients remaining lesion-free for at least 1 year and 58.3% showing no new lesions during 2-year follow-up [4]. Similarly, a randomized prospective trial of patients with facial or scalp AKs, prior BCC/SCC, or severe photodamage found that CO2 laser resurfacing, 30% trichloroacetic acid peel, and 5% 5-fluorouracil (5-FU) cream each reduced AK counts by 83% to 92% and lowered KC incidence compared with untreated controls, with no significant differences among the three active treatment groups [5].
Older patients with chronically photodamaged skin and recurrent AKs or KCs may be particularly appropriate candidates, because several mechanistic and clinical studies link age-associated dermal fibroblast senescence, reduced IGF-1 signaling, and impaired UVB response to photocarcinogenesis. Fractionated laser resurfacing in geriatric volunteers decreased senescent fibroblasts, increased dermal IGF-1 expression, and normalized the inappropriate UVB response observed in untreated geriatric skin [6]. In a later randomized clinical trial of 48 individuals aged 60 years and older with considerable actinic damage, a single unilateral fractionated laser resurfacing treatment produced a sustained reduction in AKs and fewer KCs on the treated side than on the untreated side over up to 36 months of follow-up (2 vs. 24 KCs) [7]. These findings support considering fractional laser field therapy in patients with substantial cumulative photodamage and ongoing lesion development, while recognizing that available data remain limited in size and setting [7].
Patients with field cancerization involving the face, scalp, or forearms may be candidates when the treatment goal includes both reduction of AK burden and improvement of the broader photodamaged field. A single ablative fractionated laser resurfacing treatment of one dorsal forearm, wrist, and dorsal hand in patients aged 60 years or older led to a 62% reduction in AK count at 6 months and was well tolerated without major complications [8]. In 30 male patients with multiple scalp AKs, CO2 fractional laser resurfacing increased IGF-1 levels in treated skin by approximately 60%, reduced mean AK counts by more than 75% compared with the untreated side at 4- and 6-month follow-up, and improved reflectance confocal microscopy findings, including keratinocyte disarray and scale [9]. A prospective study of 23 patients with facial photodamage, Fitzpatrick phototypes I–III, and multiple AKs found that four monthly sessions of 1927-nm thulium fractional laser significantly reduced AK counts and photoaging scores, and biopsies demonstrated reduced vertical extension of keratinocyte atypia, increased dermal thickness, and fibroplasia, without severe adverse effects [10].
Fractional lasers may also be considered when patients value a procedural approach that can address both field disease and cosmetic photodamage, although this should be framed as an adjunctive or emerging strategy rather than a proven replacement for established field therapies. In a pilot study of 10 patients with Fitzpatrick skin types I-III, multiple AKs, and extensive sun damage, non-ablative fractional resurfacing combined with topical tretinoin produced a mean 54% improvement in AK number and skin texture that persisted for approximately 6 months, and patients preferred fractional laser therapy over other field treatment modalities because of the absence of downtime [11]. Another small study of 10 patients with 31 AKs found that three sessions of 1540-nm non-ablative fractional laser improved AK severity by 79% and reduced AK counts from 31 to 17 at 3 months after the final treatment [12]. These lower-downtime approaches may be most relevant for patients with mild-to-moderate field disease, cosmetic concerns, or poor tolerance for prolonged topical inflammation, but the evidence base is smaller and follow-up is shorter than for more intensive ablative strategies [11,12].
Selecting an Ablative Versus a Non-ablative Laser
Selection between ablative and non-ablative fractional lasers should be guided by the clinical goal, field severity, anatomic site, tolerance for downtime, and whether the laser is being used alone or to enhance delivery of PDT or topical therapy. Ablative lasers such as CO2 and Er:YAG vaporize epidermal and superficial dermal tissue, which can directly remove actinically damaged tissue but may also produce greater post-procedural morbidity, including prolonged healing, erythema, infection, scarring, or dyspigmentation [4,13]. Non-ablative fractional lasers are designed to induce controlled dermal remodeling while limiting epidermal disruption, offering a lower-downtime option, although clinical effects may be more modest and the available AK/KC prevention data are less extensive [11,14].
Ablative approaches may be favored when the priority is more aggressive field resurfacing, reduction of clinically evident AK burden, or enhancement of topical photosensitizer or drug penetration. Studies of fully ablative resurfacing have reported substantial AK reductions in patients with widespread disease, including the 94% AK reduction observed after full-face CO2 and/or Er:YAG resurfacing and the 83% to 92% AK reduction observed after CO2 laser resurfacing, trichloroacetic acid peel, or 5-FU in the randomized trial described above [4,5]. Fractionated ablative resurfacing may preserve some of the biologic effects of fully ablative resurfacing while improving healing by treating microscopic columns of skin surrounded by untreated tissue [15]. In a direct molecular comparison, both fully ablative and fractionated CO2 resurfacing induced dermal remodeling and new collagen formation, but collagen induction after fractionated ablative resurfacing was approximately 40% to 50% of that after fully ablative resurfacing [15].
Non-ablative fractional lasers may be considered when the priority is tolerability, shorter recovery, and improvement of skin quality in patients with less severe field disease or lower willingness to accept downtime. Non-ablative fractionated laser resurfacing of photodamaged forearm skin induced an organized wound-healing response, with induction of proinflammatory cytokines and matrix metalloproteinase followed by type I collagen induction, and dermal remodeling was observed at both low and high microbeam energy settings [16]. As noted above, 1540-nm non-ablative fractional laser improved AK severity by 79% and reduced AK counts from 31 to 17 in a 10-patient study, and non-ablative fractional resurfacing combined with topical tretinoin improved AK number and skin texture by a mean of 54% with no reported downtime in a separate pilot study [11,12]. These findings support non-ablative fractional lasers as a potentially patient-friendly option, but the small sample sizes and limited follow-up do not support strong KC-prevention claims [11,12].
The distinction between ablative and non-ablative devices should not be reduced to “more effective” versus “safer,” because each approach answers a different clinical question. Reviews comparing resurfacing modalities generally find that ablative lasers alone are more effective than non-ablative lasers for AK treatment, and that combination therapies using ablative lasers with PDT show the greatest AK clearance, but these conclusions are limited by heterogeneity and relatively few long-term outcomes measuring recurrence or KC progression [17]. A review of laser resurfacing monotherapy similarly concluded that fully ablative CO2 and Er:YAG resurfacing appear more effective for AK treatment than fractional ablative techniques, but that larger clinical trials are needed to establish stronger evidence-based conclusions [18]. Therefore, ablative fractional lasers may be better suited to patients with severe field cancerization, thicker AKs, or a need for enhanced PDT or topical drug delivery, whereas non-ablative fractional lasers may be more appropriate for selected patients who prioritize tolerability, cosmetic improvement, and minimal downtime [17,18].
Use with Existing Therapies
Topical agents and PDT are the mainstays of field-directed treatment of AKs [19]. A growing body of evidence suggests that fractional lasers, particularly ablative fractional lasers, serve as effective adjuncts to these established therapies [20]. By creating microscopic channels through the epidermis, ablative fractional lasers (AFXL) enhance photosensitizer and topical drug penetration, allowing for shorter incubation periods without sacrificing clinical efficacy [21,22]. In one randomized trial, AFXL alone achieved a complete response rate of only 5%, compared with 74% for AFXL-assisted PDT (AFXL-PDT), establishing that the laser is an adjunct to PDT rather than a stand-alone field therapy [23].
Despite the evidence supporting combination therapy for treating AKs and field cancerization, a notable heterogeneity exists among published laser-assisted PDT protocols [20]. Studies differ in many aspects including patient population and design characteristics (Table 1A), protocol parameters (Table 1B), and primary clinical endpoints and outcomes (Table 1C) [24]. This heterogeneity reflects the evolution of fractional laser-assisted PDT and the varying needs of different patient populations; however, it also prevents direct comparison between studies and, ultimately, standardized treatment recommendations. This raises an important practical question for clinicians: how should fractional lasers be incorporated into existing field-directed treatment strategies?
Among combination approaches, AFXL-PDT has the strongest evidence base. A foundational randomized clinical trial using AFXL-PDT with methyl aminolevulinate (MAL) found that the combination was significantly more effective than MAL-PDT alone for all AK grades at 3-month follow up [25]. Subsequent work demonstrated a durable benefit: AFXL-PDT with a 3-hour incubation achieved 91.7% lesion clearance compared with 65.6% for conventional MAL-PDT at 3 months, and the difference persisted at 12 months (84.8% vs. 51.1%) [26]. These encouraging findings have been reinforced by systematic reviews and meta-analyses [20,27].
In patients with thicker lesions (grades II-III), extensive field cancerization, and immunosuppression, AFXL enhanced PDT efficacy across multiple studies [25,28,29]. This is not to say that grade I lesions or otherwise limited disease would not benefit from AFXL-PDT; one study found a significant but marginal gain in clearance of grade I lesions [25]. In such cases, patient goals and the anticipated burden and cost should be weighed carefully before adding AFXL pretreatment.
A practical advancement of AFXL pretreatment is that the laser-created microchannels can facilitate photosensitizer penetration and permit shorter incubation protocols. In patients with facial AKs, ablative fractional CO2 laser-assisted PDT with a 90-minute incubation time achieved a clearance rate of 71.4%, compared with 64.7% for conventional PDT with a 180-minute incubation, a difference that was not statistically significant between groups [30]. In another study, fractional CO2 laser pretreatment permitted a photosensitizer incubation of only 70-90 minutes, with a 70.6% complete response rate within three sessions and no significant adverse effects [31]. A randomized intraindividual comparison of field-cancerized skin found that AFXL-assisted MAL-PDT with a 1-hour incubation had 12-month preventive efficacy similar to that of conventional MAL-PDT with a 3-hour incubation, suggesting that laser pretreatment may shorten photosensitizer occlusion time without compromising prevention of new lesions over the following year [21].
More recent studies have focused on optimizing PDT with daylight-based protocols to improve patient convenience and tolerability. Daylight PDT (dPDT), which uses natural daylight or indoor illumination stimulating daylight, can reduce treatment-associated pain. Lindholm et al. compared dPDT alone with AFXL-dPDT and confirmed that AFXL pretreatment improved AK clearance at 6 months with this illumination modality [32]. However, in a separate trial, the 1-year AK clearance rate was 71.0% with simulated daylight PDT compared with 85.3% with conventional PDT, and noninferiority was not demonstrated [33]. Nevertheless, simulated dPDT was preferred by 98.3% of patients due to better pain tolerance [33]. These findings reinforce that PDT protocols should be individualized according to each patient’s priorities regarding long-term clearance, pain, and treatment setting.
Studies that specifically assess prevention of new AKs remain limited but promising. Vrani et al. counted new AKs in areas treated with AFXL-PDT or MAL-PDT alone at several time points over 1 year and reported mean times to new lesion of 9.55 ± 3.02 months for the AFXL-PDT group and 9.68 ± 2.84 months for the MAL-PDT group [21]. The difference was not significant, supporting reassessing patients who receive PDT, with or without AFXL pretreatment, at 6 to 9 months. Future studies should confirm this follow-up interval and further evaluate the preventive effect.
Less evidence exists for laser-assisted topical therapy. There is a strong mechanistic rationale that AFXL pretreatment would improve delivery of 5-FU or imiquimod, but to our knowledge no head-to-head trials have been conducted [34]. This may reflect tolerability concerns or the impracticality of pairing a multi-week home regimen with an additional in-office laser procedure. In a murine model, AFXL combined with imiquimod produced substantial clearance of SCCs. Laser-assisted topical therapy therefore represents a rich area for future study [35].
When Lasers Should Not Replace Standard Care, and Additional Safety Considerations
Fractional lasers have an emerging role in the treatment of AKs and KCs and, potentially, in KC prevention. However, clinicians must recognize when lasers do not replace the standard of care. Most importantly, lasers should never replace a timely biopsy of any lesion suspicious for malignancy. For established KCs, excision and, in selected cases, Mohs micrographic surgery remain standard treatments, while PDT and other nonsurgical options are generally reserved for cases in which surgery is undesirable or contraindicated [36]. Therefore, fractional lasers should be presented as field-directed, preventive, or adjunctive tools, not as substitutes for biopsy or guideline-based treatment of invasive or high-risk tumors [36].
Patients less likely to benefit from laser-based therapy over standard care include those with isolated AKs adequately managed with lesion-directed therapy and those unable to tolerate procedural downtime or wound care. Reviews of AK treatment emphasize that established options, including cryotherapy, PDT, imiquimod, 5-FU, trichloroacetic acid, and ablative fractional laser, all reduce AKs in immunocompetent patients, but comparative decision-making is limited by heterogeneity in outcome reporting, follow-up, body site, and patient risk [34].
In practice, laser choice should also incorporate safety considerations and anatomic site. Full-face resurfacing studies reported adverse events including transient perioral scarring, Staphylococcus aureus infection, and dyschromia, whereas newer fractional and non-ablative studies more often emphasize tolerability but still require careful parameter selection and follow-up [4,12]. The 1927-nm thulium fractional laser study in patients with facial photodamage and multiple AKs reported significant clinical and histopathologic improvement without severe adverse effects, but the study population was limited to Fitzpatrick phototypes I-III and follow-up extended only 3 months beyond the last of four monthly sessions [10]. These data support a cautious, individualized approach rather than a single standardized laser protocol for all patients with field cancerization [10].
High-Risk, Immunosuppressed Patients
High-risk patients, including organ transplant recipients (OTRs) and other immunosuppressed patients, represent an attractive but evidence-limited population for fractional laser-based field therapy. OTRs have a substantially increased risk of SCC risk and often have difficult-to-treat AKs on acral or extensively field-cancerized skin, but systematic review data indicate that evidence for nonsystemic AK therapies in this population remains limited and heterogeneous [37]. In OTRs with multiple AKs and wart-like lesions on the dorsal hands, AFXL-PDT produced a higher AK complete response than AFXL alone at 4 months (73% vs. 31%) and downgraded more AKs to lower lesion grades (82% vs. 52%) [28]. In another randomized trial in OTRs, AFXL-dPDT achieved higher 3-month complete response rates than dPDT, conventional PDT, or AFXL alone, with lower pain scores than conventional PDT but more intense transient erythema and crusting than either dPDT or conventional PDT [23]. These data support considering laser-assisted combination therapy in selected high-risk patients, but they do not yet establish fractional lasers as a stand-alone KC-preventive therapy in transplant populations [23,28,37].
Proposed Clinical Algorithm (Figure 1)
To accompany this review, we propose a clinical algorithm (Figure 1) that synthesizes the available evidence into a practical framework for using fractional lasers in the treatment of AKs and field cancerization. The algorithm is organized as a series of decision levels: whether the patient is an appropriate candidate for fractional laser field-directed therapy (Level 0); whether AFXL pretreatment before PDT is warranted (Level 1); selected of the illumination and incubation protocol, which are chosen together (Level 2); treatment administration, for which device settings, session number, and technique remain unstandardized (Level 3); and follow-up, with reassessment recommended at 6 to 9 months (Level 4). The supporting evidence for each branch is summarized within the figure.

Limitations and Future Directions

The current literature on fractional lasers for AK and KC prevention has several limitations. Many studies enrolled small patient populations, and there is substantial heterogeneity in laser type, device settings, treatment protocols, follow-up periods, and outcome measures. This makes it difficult to compare results directly between studies or to define a standardized approach to fractional laser use in patients with field cancerization.
Another important limitation is the lack of long-term data measuring the development of KC. Although several studies have shown reductions in AK burden following fractional laser treatment, most have focused primarily on AK clearance over relatively short follow-up periods. A few studies have reported fewer KCs following laser treatment, but this evidence remains limited in size and duration. Reduction in AK burden may plausibly decrease subsequent KC risk, but AK clearance should not be interpreted as direct evidence of KC prevention. Longer-term studies measuring incident BCC and SCC are needed to determine whether the reduction in AKs translates to a reduction in KC development. The available evidence is also limited to certain patient populations. Several studies enrolled only patients with Fitzpatrick skin types I-III, and evidence in immunosuppressed and OTR populations also remains limited and heterogeneous, making it difficult to determine whether the findings generalize across patient populations and clinical settings.
Future studies should prioritize determining whether the reduction in AK burden following fractional laser treatment translates into a reduction in subsequent KC development. They should also adopt more standardized laser settings, treatment protocols, follow-up periods, and outcome measures so that results can be compared across studies. Longer follow-up would help determine whether reductions in AK burden are sustained over time, whether and when retreatment is required, and the optimal follow-up interval after PDT with or without laser pretreatment. Finally, the clinical algorithm proposed in this review was developed based on a synthesis of the current evidence and has not been externally validated; prospective studies evaluating its use in practice would be valuable.

Conclusion

Fractional lasers represent a promising field-directed approach for patients with extensive actinic damage and AKs, particularly those with recurrent lesions or a high burden of field cancerization. Current studies demonstrate that both ablative and non-ablative fractional lasers can reduce AK burden, and that combining ablative fractional lasers with PDT may further improve AK clearance and allow for shorter incubation protocols. However, the current evidence is limited by small study populations, heterogeneous treatment protocols, and limited long-term follow-up.
Although reducing AK burden may plausibly decrease the risk of subsequent KC, long-term studies measuring the development of BCC and SCC are needed to confirm this. The framework proposed here is intended to help dermatologists select appropriate patients, choose between ablative and non-ablative devices, and integrate lasers with existing therapies while stronger evidence accumulates. Overall, fractional lasers should be viewed as an emerging field-directed or adjunctive treatment rather than a replacement for established therapies or for the standard management of suspicious lesions.

Funding

This research received no external funding.

Data Availability Statement

No new data were generated or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.
AI Disclosure: ChatGPT (OpenAI) assisted with editing text and organizing references. The authors reviewed the resulting material and take responsibility for the accuracy, originality, and integrity of the submitted work.

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Table 1. A: Study Characteristics.
Table 1. A: Study Characteristics.
Study/Year Design Patients / AKs Population Anatomic Site AK Grade
Togsverd-Bo 2012 [25] Split-field RCT 15 / 212 Immunocompetent Face, scalp I-III
Helsing 2013 [28] Split-field RCT 10 / 680 OTRs Dorsal hands I-III
Ko 2014 [29] Parallel-group RCT 40 / 236 Korean Patients face I-III
Togsverd-Bo 2015 [23] Split-field RCT 16 / 542 OTRs Scalp, chest, extremities I-III
Choi 2015 [26] Parallel-group RCT 88 / 427 Korean patients Face, scalp I-III
Song HS 2015 [30] Parallel-group RCT 46 / 69 Korean patients Face I-III
Wenande 2019 [38] Split-field RCT 18 / 832 Immunocompetent patients
Large skin areas with AKs and photodamage
Vrani 2019 [21] Split-field RCT 42 Greek immunocompetent patients Face, scalp NR
Falkenberg 2021 [39] Single arm interventional study 28 German immunocompetent patients Face, scalp NR
Lonsdorf 2022 [40] Split-field RCT 18 / 172 German OTRs Face, scalp I-III
Lindholm 2023, 2026 [32,41] Split-field RCT 56 / 508 Immunosuppressed patients, not including OTRs Face, scalp I-III
Sjoholm 2026 [33] Split-field RCT 69 / 1458 Immunocompetent + immunosuppressed Face, scalp, torso, upper extremities I-II
Abbreviations: AK, Actinic keratosis; NR, Not reported; OTR, Organ transplant recipient; RCT, Randomized controlled trial
B: Protocol Parameters.
Study Laser Platform Laser Parameters Photosensitizer Incubation Time Illumination Protocol
Togsverd-Bo 2012 [25] Fractional CO2 laser (UltraPulse, Lumenis) 10 mJ per pulse, 0.12 mm spot, 5% density, single pulse MAL 3 hours cPDT
Helsing 2013 [28] Fractional CO2 laser (Lutronic)
 First-pass: 160 mJ per pulse, 625-ms pulse duration and 53% coverage (nonatrophic skin); 140 mJ per pulse, 565-ms pulse duration, 52% coverage (atrophic skin).
Second pass: 60 mJ per pulse, 206-ms pulse duration, 52% coverage (nonatrophic skin); 40 mJ per pulse, 132-ms pulse duration and 43% coverage (atrophic skin).		 MAL 3 hours cPDT
Ko 2014 [29] 2940 nm Ablative fractional erbium: YAG laser (JOULE) Ablation depth 300-550 μm using level 1 coagulation, 22% treatment density and a single pulse MAL 3 hours cPDT
Togsverd-Bo 2015 [23] 2940 nm ablative fractional laser 2.3 mJ per pulse, 1.15 W, two stacks, 50-μs pulse-duration, 2.4% density. MAL 2.5 hours (AFXL-dPDT and dPDT)
3 hours (cPDT) 		cPDT, dPDT
Choi 2015 [26] 2940-nm Er:YAG AFXL (Joule) 300–550 μm ablation depth, level 1 coagulation, 22% treatment density and a single pulse. MAL 2 hour vs 3 hour cPDT
Song HS 2015 [30] Ablative fractional CO2 laser (Lutronic) wavelength of 10 600 nm, pulse energy of 50 mJ, spot density of 100 spots/cm2, power of 30W, and beam size of 120 μm MAL 90 min (AFXL-PDT) vs 180 min (PDT) cPDT
Wenande 2019 [38] 2940-nm Er:YAG laser (Joule) Single pass, 22% density, varied pulse energy based on AK grade, (40–200 μm) MAL 2 hour daylight exposure dPDT
Vrani 2019 [21] Ablative (Spectra-SP MAX) wavelength of 10 600 nm, char-free operation mode, power 30 W, pulse width 100 μ/s, repetition rate 100 Hz, spot density 11 × 11(121 spots/cm2) and beam size of 120 μm MAL 1 hour incubation (AFXL group), 3 hours cPDT cPDT
Falkenberg 2021 [39] Ablative fractional CO2 laser (Lutronic) pulse energy 8 mJ, spot density 50 spots/cm2, power 30 W, beam size 4−18 mm ALA 1 hour SDL-PDT
Lonsdorf 2022 [40] Ablative fractional Er:YAG (MCL 31 Dermablate) C10%, 10×4.0 J/cm2, 100 μs, 1 pass MAL 3 hours cPDT, low-irradiance PDT
Lindholm 2023, 2026 [32,41] ablative fractional CO2 laser (Candela) 19 W, Dot mode, spacing 1,000 μm, stack 3, scanning dwell time 1800 μs, repeat 0.5 s MAL 2 hours dPDT
Sjoholm 2026 [33] NA NA ALA ≤30 min (SDL-PDT, no occlusion) vs. 3 hour (cPDT, occluded) cPDT, SDL-PDT
Abbreviations: AFXL, Ablative fractional laser; ALA, 5-Aminolevulinic acid; cPDT, conventional photodynamic therapy; dPDT, daylight photodynamic therapy; NA, Not Applicable; MAL, Methyl aminolevulinate; PDT, photodynamic therapy; SDL-PDT, simulated daylight PDT
C: Outcomes.
Study Treatment Arms Outcome and Follow-up Results P-value Safety and Tolerability
Togsverd-Bo 2012 [25] AFXL-PDT vs cPDT Grade I lesion CR at 3 months 100%; 80% 0.04 Pain scores during illumination, erythema and crusting were increased with AFXL-PDT; long-term pigmentary changes with AFXL-PDT than cPDT, but NS
Togsverd-Bo 2012 [25] AFXL-PDT vs cPDT Grade II-III lesion CR at 3 months 88%; 59% 0.02 Same as above
Helsing 2013 [28] AFXL-PDT vs AFXL alone Lesion CR at 4 months
 73%, 31% 0.002 Mild pigment changes in 4 patients (3 AFXL-PDT, 1 AFXL); no scarring; patient overall preference favored AFXL-PDT
Ko 2014 [29] AFXL-PDT vs cPDT Lesion CR at 3 months 86.9%, 61.2% 0.001 Mean pain score of AFXL-PDT group was increased but not statistically significant. Local adverse events more frequent and intense in AFXL-PDT group. Hyperpigmentation and erythema was more persistent in AFXL-PDT group (NS).
Togsverd-Bo 2015 [23] AFXL-dPDT vs dPDT vs cPDT vs AFXL alone Lesion CR at 3 months 74%, 46% (dPDT), 50% (cPDT), 5% (AFXL alone) <0.001 (4-arm); 0.004 (3 PDT arms) Median maximal pain 0 (AFXL-dPDT, dPDT, AFXL) vs. 5 (cPDT), p < 0.001; erythema and crusting more intense after AFXL-dPDT than dPDT or cPDT
Choi 2015 [26] 2-h AFXL-PDT vs 3-h AFXL-PDT vs 3-h cPDT Lesion CR at 3 and 12 months 3h-AFXL-PDT 91.7% / 84.8%; 2h-AFXL-PDT 76.8% / 67.5%; 3h-cPDT 65.6% / 51.1% 0.001 (3h-AFXL vs. others, both timepoints); 0.038 (2h-AFXL vs. MAL-PDT at 3 months) No significant differences in pain or adverse events
Song HS 2015 [30] AFXL-PDT vs cPDT Lesion CR at 10 weeks 71.4%, 64.7% 0.55 Most patients experienced tolerable pain without differences in pain score, erythema, or crusting
Wenande 2019 [38] AFXL-dPDT vs microdermabrasion-dPDT Lesion CR at 3 months 81%, 60% < 0.001 AFXL-PDT had lower pre-treatment related pain (p = 0.002) and superior cosmetic outcomes (p = 0.035) and more intense local skin reactions (p = 0.004)
Vrani 2019 [21] AFXL-PDT vs cPDT # of new AKs at 3, 6, 9, 12 months 90.5% → 48% (3 to 12 month follow up); mean time to new lesion 9.55 ± 3.02 months; 93% → 52%; mean time 9.68 ± 2.84 months NS at every timepoint No severe adverse events were recorded during treatment or follow up
Falkenberg 2021 [39] simulated-PDT with AFXL pretreatment Lesion count and AKASI reduction at 3 months 91.3%; Median AKASI reduction rate 75.5% < 0.0001 No significant changes in vital signs.Treatment-related adverse events were found in 21.4% of patients
Lonsdorf 2022 [40] low-irridance AFXL-PDT vs cPDT Lesion count and AKASI reduction at 3 months Mean LRR 77.3 ± 23.6%; trend toward greater AKsI reduction; 61.8 ± 21.4% 0.025 (LRR); AKsI difference NS. Both arms reduced AK count vs. baseline (p < 0.0005 each) No significant pain increase, but with more interruption requests and two early terminations in the AFXL arm
Lindholm 2023 [32] AFXL-dPDT vs dPDT Lesion CR, complete and partial field clearance at 6 months 86.2%; 50.0%; 78.6%
70.2%; 30.3%; 50.0%
 <0.01; 0.04 ; <0.01 Illumination pain equivalent (NRS 1.2 vs. 1.1, p = 0.71)
Lindholm 2026 [41] AFXL-dPDT vs dPDT Lesion CR at 24 months 56.3%, 43% 0.003 NR
Sjoholm 2026 [33] cPDT vs SDL-PDT Lesion CR at 12 months 71%, 85% < 0.001 SDL-PDT caused significantly less pain (mean numeric scale 6.6 vs 0.8) p < 0.001
Abbreviations: AFXL, Ablative fractional laser; cPDT, conventional photodynamic therapy; dPDT, daylight photodynamic therapy; MAL, Methyl aminolevulinate; NR, Not reported; PDT, photodynamic therapy;
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