Carbon Dioxide Laser for Actinic Lesions and Other Selected Indications

Number: 0427

Policy

Aetna considers carbon dioxide laser treatments medically necessary for the following indications:

• Condyloma
• Individuals with melanoma who have in-transit metastases and palliative surgery is not feasible
• Primary penile tumor (clinical stage Tis, Ta, and T1 Grade 1 to 2)
• Refractory plantar warts (verruca plantaris)
• Removal of actinic keratoses for members who meet applicable criteria set forth in CPB 0567 - Actinic Keratoses Treatments.
• Removal of superficial basal cell carcinomas of the skin.

Aetna considers carbon dioxide laser treatments of other actinic lesions as cosmetic.  Note: Most Aetna benefit plans exclude coverage of cosmetic procedures.

Aetna considers carbon dioxide laser surgery experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Aphthous stomatitis
• Cutaneous angiokeratomas
• Cutaneous leishmaniasis
• Elephantiasis nostras verrucosa
• Female sexual dysfunction
• Hailey-Hailey disease
• Hidradenitis suppurativa (including scarring)
• Linear epidermal nevus
• Male androgenetic alopecia
• Onychomycosis
• Oral potentially malignant disorders
• Peri-implantitis
• Port wine stains
• Stress urinary incontinence
• Vaginal atrophy and dysparenuria (e.g., the diVa laser vaginal therapy and the MonaLisa Touch Laser (fractional CO₂ laser)).

Aetna considers fractional carbon dioxide laser medically necessary for the treatment of hypertrophic burn scars, traumatic scars, and surgical scars when conventional therapies (e.g., compression garments, corticosteroid injections, and silicone gel/sheeting) have failed. See CPB 389 - Hypertrophic Scars and Keloids.

Aetna considers fractional carbon dioxide laser for actinic keratoses, morphea (localized scleroderma), and vulvovaginal atrophy symptoms and vaginal rejuvenation in peri-menopausal women experimental and investigational because its effectiveness for these indications has not been established.

Aetna considers fractional CO₂ laser combined with narrow-band ultraviolet B phototherapy for the treatment of non-segmental vitiligo experimental and investigational because the effectiveness of this approach has not been established.

Background

The CO₂ laser is effective in removing actinic keratoses and superficial basal cell carcinomas of the skin.  Use of the CO₂ laser to treat non-precancerous actinic lesions, such as skin wrinkling, is considered cosmetic, and thus subject to the standard contractual exclusion of coverage for cosmetic procedures.

A recent review on laser and photodynamic therapy for the treatment of non-melanoma skin cancer (Marmur et al, 2004) stated that at this time, because the reported recurrence rates are significantly higher than those achieved with standard therapies, laser and photodynamic therapy should be reserved for only those patients who can not undergo surgical therapy for basal cell carcinoma and squamous cell carcinoma.

Iyer et al (2004) evaluated the effectiveness of full face laser resurfacing (UPCO₂ and/or Er:Yag laser) in reducing the number of facial actinic keratoses by comparing pre-operative and post-operative numbers of lesions present and to observe the incidence of non-melanoma skin cancer after full face laser resurfacing (n = 24).  These investigators concluded that full face laser resurfacing provides long-term effective prophylaxis against actinic keratoses and may reduce the incidence of actinic keratoses-related squamous cell carcinoma.  The findings of this study need to be validated by well-designed trials with long-term follow-up.

Krakowski et al (2014) noted that hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin condition that can have a significant psychosocial impact, both with the active disease and with residual scarring.  Although a wide variety of treatment options exist for HS, to the authors’ knowledge there are no reported modalities aimed specifically at treating HS scarring.  These researchers described the case of an adolescent female who received medical management of intra-mammary HS followed by successful treatment with fractionated 10,600-nm CO₂ laser for her residual cribriform scarring.  The authors believed there is great potential for the use of fractionated CO₂ laser to improve short- and long-term psychosocial outcomes of HS, promote physical scar remodeling, and possibly alter the disease process itself.

In a systematic review, Ledon et al (2014) stated that onychomycosis is a prevalent and extremely difficult condition to treat.  In older and diabetic populations, severe onychomycosis may possibly serve as a nidus for infection, and other more serious complications may ensue.  Many treatment modalities for the treatment of onychomycosis have been studied, including topical lacquers and ointments, oral anti-fungals, surgical and chemical nail avulsion, and lasers.  Due to their minimally invasive nature and potential to restore clear nail growth with relatively few sessions, lasers have become a popular option in the treatment of onychomycosis for both physicians and patients.  Laser or light systems that have been investigated for this indication include the CO₂, neodymium-doped yttrium aluminum garnet, 870/930-nm combination, and femtosecond infrared 800-nm lasers, in addition to photodynamic and ultraviolet light therapy.

Furthermore, an UpToDate review on “Onychomycosis” (Goldstein, 2014) states that “Although neodymium-doped:yttrium aluminum garnet (Nd:YAG) and diode lasers have emerged as treatment options for onychomycosis, data on the efficacy of these interventions are limited and the mechanisms of action and optimal regimens for these treatments remain unclear.  Until more robust data supporting the efficacy of laser therapy for onychomycosis is available, we cannot recommend the routine use of this modality”.

In a Cochrane review, Kaushik et al (2014) evaluated the safety and effectiveness of surgical interventions in women with high-grade vulval intraepithelial neoplasia (VIN).  These investigators searched the Cochrane Gynaecological Cancer Group Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 11, 2013 and MEDLINE and EMBASE up to December 2013.  They also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies, and contacted experts in the field.  Randomized controlled trials (RCTs) that compared surgical interventions in adult women diagnosed with high-grade VIN were selected for analysis.  Two review authors independently abstracted data and assessed risk of bias.  They identified 1 RCT (n = 30) that met the inclusion criteria; this trial reported data on CO₂ laser surgery versus cavitational ultrasonic surgical aspiration (CUSA).  There were no statistically significant differences in the risks of disease recurrence after 1 year of follow-up, pain, scarring, dysuria or burning, adhesions, infection, abnormal discharge or eschar between women who underwent CO₂ laser surgery and those who received CUSA.  The trial lacked statistical power due to the small number of women in each group and the low number of observed events, but was at low risk of bias.  The authors concluded that the included trial lacked statistical power due to the small number of women in each group and the low number of observed events.  The absence of reliable evidence regarding the safety and effectiveness of the 2 surgical techniques (CO₂ laser surgery and CUSA) for the management of VIN therefore precluded any definitive guidance or recommendations for clinical practice.

Carbon Dioxide Laser for Hailey-Hailey Disease

Falto-Aizpurua et al (2015) stated that benign familial chronic pemphigus, or Hailey-Hailey disease (HHD), is a recurrent bullous dermatitis that tends to have a chronic course with frequent relapses.  Long-term treatment options include surgery with skin grafting or dermabrasion.  Both are highly invasive and carry significant risks and complications.  More recently, “laser-abrasion” has been described as a less invasive option with a better side-effect profile.  These investigators systematically reviewed the safety and effectiveness of carbon dioxide laser therapy as a long-term treatment option for HHD, and provided a review of other lasers that have been reported with this goal.  A total of 23 patients who had been treated with a carbon dioxide laser were identified.  After treatment, 10 patients (43 %) had had no recurrence, 10 (43 %) had greater than 50 % improvement, 2 (8 %) had less than 50 % improvement and 1 (4 %) patient had no improvement at all (follow-up period ranged from 4 to 144 months).  Laser parameter variability was wide and adverse effects were minimal, including dyspigmentation and scarring.  The authors concluded that reviewed evidence indicated this therapy offers a safe, effective treatment alternative for HHD with minimal risk of side-effects.  Moreover, they stated that larger, well-designed studies are needed to determine the optimal treatment parameters.

Also, an eMedicine review on “Familial Benign Pemphigus (Hailey-Hailey Disease) Treatment & Management” (Helm, 2014) noted that “A single case report of remission induced by multiple treatments of long-pulsed alexandrite laser brings additional promise of potential long-term control, though many more studies are needed”.  The review did not mention carbon dioxide laser as a therapeutic option.

Furthermore, an UpToDate review on “Hailey-Hailey disease (benign familial pemphigus)” (Morrell, 2015) states that “Surgical and destructive methods have been used in patients with recalcitrant HHD and include carbon dioxide laser or 595 nm pulsed dye laser ablation …. Long healing time, pain, scarring, and uncertain long-term benefit are drawbacks of surgical or destructive therapies for HHD”.

Falto-Aizpurua and colleagues (2015) noted that benign familial chronic pemphigus, or HHD, is a recurrent bullous dermatitis that tends to have a chronic course with frequent relapses. Long-term treatment options include surgery with skin grafting or dermabrasion.  Both are highly invasive and carry significant risks and complications.  More recently, 'laser-abrasion' has been described as a less invasive option with a better side-effect profile.  These investigators systematically reviewed the safety and effectiveness of CO₂ laser therapy as a long-term treatment option for HHD, as well as provided a review of other lasers that have been reported with this goal.  A total of 23 patients who had been treated with a CO₂ laser were identified.  After treatment, 10 patients (43 %) had had no recurrence, 10 (43 %) had greater than 50 % improvement, 2 (8 %) had less than 50 % improvement and 1 (4 %) patient had no improvement at all (follow-up period ranged from 4 to 144 months).  Laser parameter variability was wide and adverse effects were minimal, including dyspigmentation and scarring.  The authors concluded that reviewed evidence indicated this therapy offers a safe, effective treatment alternative for HHD with minimal risk of side-effects.  Moreover, they stated that larger, well-designed studies are necessary to determine the optimal treatment parameters.

Melanoma

National Collaborating Centre for Cancer’s clinical practice guideline on “Melanoma: Assessment and management” (2015) states that if palliative surgery is not feasible for people with in-transit metastases, CO₂ laser is a management option.

Peri-Implantitis

Natto et al (2015) evaluated the effectiveness of various types of lasers (Nd:YAG, CO2, diode, erbium/chromium-doped yttrium-scandium-gallium-garnet [Er,Cr:YSGG], and erbium-doped yttrium-aluminum-garnet [Er:YAG]) in the treatment of peri-implantitis and their use in surgical and non-surgical procedures. Human studies for the treatment of peri-implantitis with laser therapy, published between 2002 and January 2014, were collected utilizing the electronic databases PubMed, Ovid, MEDLINE, Cochrane, and Google Scholar.  Two reviewers conducted the study selection, data collection, and validity assessment.  A total of 812 studies were selected in the initial title search; 13 studies were then chosen for this review.  No human studies evaluated the effect of the Nd:YAG laser on peri-implantitis.  The CO₂ laser was reported to be safe and able to enhance bone regeneration.  The diode laser (980 nm) appeared to be effective in its bactericidal effect without changing the implant surface pattern.  The Er,Cr:YSGG laser was reported to obtain bone regeneration around a failing implant in 1 case, while the Er:YAG laser exhibited a strong bactericidal effect against periodontopathic bacteria at a low energy level.  The authors concluded that although lasers have shown promising results in reducing clinical signs of peri-implantitis, because of the limited sample sizes and short follow-up periods, no firm conclusion can be drawn at this moment.  They stated that there is a need for more well-designed, longitudinal, RCTs.

Port Wine Stains

Lanigan and Cotterill (1990) noted that the CO₂ laser was used to treat 51 patients with port-wine stain (PWS); 29 patients were adults who had failed to respond to argon or continuous wave dye laser therapy and 22 patients were children with pink PWS. Follow-up assessment of 40 patients 12 months after treatment revealed an excellent or good result in 74 % of adults and 53 % of children.  The authors concluded that the results observed in adult “therapeutic failures'” was encouraging and CO₂ laser therapy can be advised for this group.  Two children had a poor result, 1 with a hypertrophic scar, and treatment in this age group with the CO₂ laser should be considered with caution.

In a Cochrane review, Faurschou et al (2011) studied participant satisfaction, clinical efficacy, and adverse effects of the treatment of PWSs by lasers and light sources. These investigators searched the following databases up to April 2010: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (Clinical Trials) in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2007), LILACS (Latin American and Caribbean Health Science Information database, from 1982), and reference lists of articles.  They also searched online trials registries for ongoing trials and contacted trial authors where appropriate.  Randomized clinical trials (RCTs) of lasers or light sources for the treatment of PWSs were selected for analysis.  The outcomes of interest were participant satisfaction, reduction in redness of the PWS as determined by clinical evaluation, and short- and long-term adverse effects of the treatments; 3 authors independently extracted data and assessed trial quality.  These researchers included 5 RCTs involving a total of 103 participants; all of the trials used a within-participant design.  The interventions and outcomes were too varied to be combined statistically.  All trials used the pulsed dye laser for comparisons.  None of the studies focused on participant satisfaction, which was one of the primary outcomes, but participant preference was evaluated in 3 of 5 studies.  Participants preferred the pulsed dye laser to intense pulsed light based on the clinical effect.  They marginally preferred the Neodymium:YAG (yttrium-aluminum-garnet) (Nd:YAG) laser to the pulsed dye laser due to shorter lasting purpura, and pulsed dye laser in conjunction with cooling was preferred to treatment with pulsed dye laser alone.  All trials examined short-term efficacy of less than 6 months after treatments with the pulsed dye laser, intense pulsed light, and Nd:YAG laser.  The pulsed dye laser was evaluated in all 5 trials.  Depending upon the setting of the pulsed dye laser, this resulted in more than 25 % reduction in redness.  This was after 1 to 3 treatments for up to 4 to 6 months post-operatively in 50 % to 100 % of the participants.  There was only 1 study each of intense pulsed light and Nd:YAG laser.  Two trials had no occurrence of long-term adverse effects, i.e. 6 months after treatment.  Three trials reported pigmentary alterations in 3 % to 24 % of the participants, with the highest percentage occurring in Chinese participants with darker skin types.  In 1 study, 1 participant experienced scarring of the skin caused by a too-high dose of the laser used.  Short-term side-effects included pain, crusting, and blistering in the first 2 weeks after treatment.  The authors concluded that the pulsed dye laser led to clinically relevant clearance of port-wine stains.  A limited number of RCTs evaluated the efficacy from intense pulsed light and other laser types.  They stated that high-quality RCTs are needed to assess individual efficacy from different lasers and light sources, as well as participant satisfaction.

In an eMedicine review on “Capillary Malformation Treatment & Management”, Antaya (2014) stated that “Flashlamp-pumped pulsed-dye laser (PDL) surgery is the treatment of choice for capillary malformations …. Earlier laser therapies that caused an unacceptably high rate of scarring are not recommended; these therapies include carbon dioxide laser, copper vapor laser, and argon laser”.

Furthermore, an UpToDate review on “Capillary malformations (port wine stains): Clinical features, diagnosis, and associated syndromes” (Galbraith, 2016) states that “Pulsed dye laser (PDL) therapy is considered the standard of care for the treatment of capillary malformations. It is based on the concept of selective photothermolysis with oxyhemoglobin as the target.  PDL treatment irreversibly damages the capillary vessel wall with minimal damage to the overlying epidermis, which leads to lightening of the port wine stain without scarring”.  It does not mention CO2 laser as a therapeutic option.

Primary Penile Tumors

Maranda and colleagues (2016) stated that erythroplasia of Queyrat (EOQ) is a squamous cell carcinoma in-situ most commonly located on the glans penis or prepuce.  Erythroplasia of Queyrat accounts for approximately 10 % of all penile malignancies and may lead to invasive squamous cell carcinoma.  Standard therapy includes local excision, partial or total penectomy, cryotherapy, and topical cytotoxic agents.  Treatment of EOQ has proven to be challenging due to low response rates and recurrence.  In addition, radical procedures can significantly affect sexual function and quality of life (QOL).  Alternative laser treatments and PDT offer promising results for treating EOQ.  These investigators performed a systemic review of the literature for articles discussing laser and light therapy for EOQ.  Among the patients treated with the CO2 laser, 81.4 % of cases had complete remission after 1 session of treatment.  Patients treated with photodynamic therapy (PDT) presented with more variable results, where 62.5 % of those treated with methyl aminolevulinate (MAL)-PDT achieved complete remission; ALA-PDT treatment showed a similar rate of remission at 58.3 %.  One study utilized the Nd:YAG laser, which resulted in a recurrence of the lesion in 4 of the 5 patients treated.  Of the methods reviewed, the CO2 laser offered the most promising results with a cosmetically excellent prognosis.  The authors concluded that further studies with larger power and longer follow-up times are needed to determine the optimal treatment regimen for this penile malignancy.

Zreik and associates (2017) evaluated the outcome of CO2 laser treatment of penile intraepithelial neoplasia (PeIN).  These researchers performed a retrospective review of 47 patients who underwent CO2 laser ablation of PeIN, from May 2008 to June 2015.  All patients underwent acetic acid mapping and had their lesions ablated with a Lumenis Shaplan CO2 laser device.  Patients had regular follow-up and further suspicious areas underwent re-biopsy.  After laser treatment, 8 men (17 %) had a recurrence and the average time to recurrence was 19.4 months; 7 of the 8 patients with recurrences, pathologically had further PeIN and 1 patient developed G1 pT1 disease.  These patients underwent further laser treatment, glans resurfacing or local excision.  No patients required penectomy.  The average length of follow-up was 29 months (range of 1 to 76).  Penile cancer-specific survival was 100 % and overall survival (OS0 was 98 %.  No patients required re-admission or developed other long-term complications, such as meatal stenosis from their treatment.  The authors concluded that CO2 laser treatment for PeIN is effective due to its 100 % response rate, low progression rate and lower recurrence rate compared with topical agents.  The laser has minimal morbidity with cosmetically acceptable outcomes compared to more invasive resurfacing surgeries.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Penile cancer” (Version 1.2017) recommends the use of therapeutic laser (CO2, Nd:YAG, and KTP) to treat selected (clinical stage Tis, Ta, and T1 Grade 1 to 2) primary penile tumor (category 2B recommendation).

Cutaneous Angiokeratomas

Nguyen and colleagues (2017) noted that angiokeratomas can present therapeutic challenges, especially in cases of extensive lesions, where traditional surgical methods carry high risks of scarring and hemorrhage.  Argon, pulsed dye (PDL), neodymium-doped yttrium aluminum garnet (Nd:YAG), copper vapor, potassium titanyl phosphate, CO2, and erbium-doped yttrium aluminum garnet (Er:YAG) lasers have emerged as alternative options.  These researchers reviewed the use and efficacy of lasers in treating angiokeratomas.  A PubMed search identified randomized clinical trials, cohort studies, case series, and case reports involving laser treatment of cutaneous angiokeratomas.  A total of 25 studies were included.  Quality ratings were assigned using the Oxford Centre for Evidence-Based Medicine scheme.   Several laser modalities were effective in treating multiple variants of angiokeratomas.  Vascular lasers like PDL, Nd:YAG, and argon were the most studied and of these, PDL offered the safest side effect profile.  Nd:YAG may be more effective for hyperkeratotic angiokeratomas.  Combination treatment with multiple laser modalities had also demonstrated some success.  The authors concluded that lasers are a promising therapeutic option for angiokeratomas, but current use is limited by the lack of treatment guidelines.  They stated that there are limited high quality studies comparing laser treatments to each other and to non-laser options; additional studies are needed to establish guidelines and to optimize laser parameters.

Cutaneous Leishmaniasis

Palumbo (2009) stated that cutaneous leishmaniasis is the most common form of leishmaniasis.  It is a skin infection caused by a single-celled parasite that is transmitted by sand fly bites.  There are about 20 species of Leishmania that may cause cutaneous leishmaniasis.  Some Leishmania species are closely linked to humans and are therefore found in cities (Leishmania tropica), whereas some are more traditionally associated with animal species and are therefore considered zoonoses (Leishmania major).  The evidence for optimal treatment of cutaneous leishmaniasis is patchy.  Although the cutaneous form of the disease is often self-limiting, it does result in significant scarring and can spread to more invasive, mucocutaneous disease.  Therefore, treatment may be considered to prevent these complications.  The author discussed drugs for systemic and topical treatment with regard to their application, use, and adverse effects.

A Cochrane review on “Interventions for Old World cutaneous leishmaniasis” (Heras-Mosteiro et al, 2017) does not mention CO2 laser as a therapeutic option.  Furthermore, an UpToDate review on “Cutaneous leishmaniasis: Treatment” (Aronson, 2018) does not mention CO2 laser as a therapeutic option.

Elephantiasis Nostras Verrucosa

Robinson and colleagues (2018) stated that elephantiasis nostras verrucosa (ENV) is a disfiguring skin condition that is difficult to treat.  Existing treatment modalities serve to improve cosmesis or treat symptoms.  These investigators reported a case of ENV with lymphocutaneous fistula successfully treated with ablative CO2 laser.  A 57-year old woman with biopsy-proven ENV with lymphocutaneous fistula was treated with ablative CO2 laser to the symptomatic area of her right thigh in 3 treatment sessions over 6 months.  The patient had resolution of lymphocutaneous drainage as well as 90 % improvement in the appearance of ENV lesions at the 1-month follow-up visit.  The authors concluded that ablative CO2 laser may provide cosmetic, symptomatic, and medical benefit for patients with localized ENV.  These preliminary findings need to be validated by well-designed studies.

Female Sexual Dysfunction

Weinberger and associates (2019) stated that female sexual dysfunction (FSD) is a highly prevalent condition.  Nevertheless, the scientific literature has only recently begun to accumulate evidence for treatment modalities that address the underlying etiologies of FSD.  In a systematic review, these investigators elucidated what treatments are effective across the various symptom complexes of FSD.  Utilizing meta-analysis of observational studies in epidemiology guidelines, these researchers conducted a systematic review of PubMed, Embase, clinicaltrials.gov, and the Cochrane Review databases.  A total of 11 search strings, encompassing the terms "female sexual dysfunction" and "treatment", in combination with "vulvovaginal atrophy", "vaginismus", "vaginal atrophy", "vulvodynia", "vestibulitis", "hypoactive sexual desire", "arousal disorder", "sexual pain disorder", "genitourinary syndrome of menopause" and "orgasmic disorder" were utilized.  A total of 605 relevant articles were retrieved; and 103 original studies met inclusion criteria.  A total of 42 treatment modalities were utilized, including 26 different classes of medications.  Although outcome measures varied, the most substantial improvement across multiple studies was noted with various hormonal regimens.  The most common treatments included hormonal therapy (25 studies), phosphodiesterase type-5 inhibitors (9 studies), botulinum toxin A (5 studies), and flibanserin (5 studies).  The psychotherapeutic approach was detailed in 36 articles while 3 studies utilized homeopathic treatments.  Numerous treatments showed efficacy in a single-case series, including the promising results associated with the micro-ablative CO2 laser.  Despite the marked improvement in specific FSD domains, neither pharmacologic treatments nor psychotherapeutic interventions demonstrated consistent disease resolution.  The authors concluded that treatment of FSD is multi-factorial; medications alone did not resolve FSD.  The wide variability of treatment and outcome measures across the literature attested to the complexity of FSD and the need for a treatment algorithm that addresses all 4 domains of FSD.

Hidradenitis Suppurativa

Saunte and Jemec (2017) reviewed the diagnosis, epidemiology, and treatment of hidradenitis suppurativa (HS) with an emphasis on advances in the last 5 years.  A literature search was conducted using PubMed, Medline (Medical Subject Headings [MeSH]), and Embase to include recently published treatment studies (searched from September 1, 2011, to May 1, 2017).  Reviews, guidelines, conference abstracts, and studies with less than 10 patients were excluded.  Furthermore, internet searches for guidelines on HS using Baidu, Bing, Google, and Qwant browsers were performed.  The diagnosis of HS is made by lesion morphology (nodules, abscesses, tunnels, and scars), location (axillae, inframammary folds, groin, peri-genital, or perineal), and lesion progression (2 recurrences within 6 months or chronic or persistent lesions for greater than or equal to 3 months).  Hidradenitis suppurativa is more common than was previously thought based on epidemiological analysis (0.05 % to 4.10 %).  Disability from HS can be significant.  Patients with HS may have significant co-morbidities (e.g., obesity, metabolic syndrome, diabetes, and arthritis) and increased all-cause mortality (incidence rate ratio, 1.35 [95 % confidence interval [CI]: 1.15 to 1.59]).  Antibiotic treatment with combinations of clindamycin and rifampicin, or ertapenem followed by combination rifampicin, moxifloxacin, and metronidazole for 6 months is effective.  Adalimumab is effective in a significant proportion of patients and treatment with interleukin-1 (IL-1) and IL-12 receptor subunit beta 1 (Rb1) antibodies may also be useful.  Tissue-sparing surgical techniques and CO2 laser treatments also are available, but the evidence on clinical outcomes with these approaches is limited.

Oral Potentially Malignant Disorders

Cloitre and colleagues (2018) noted that oral cancer is a public health issue worldwide.  Oral potentially malignant disorders (OMPDs) are lesions of the oral mucosa that are predisposed to malignant transformation.  The mainstay of OMPDs treatment around the world is now the CO2 laser but the reported recurrence and malignant transformation rates vary widely in the literature.  These researchers estimated the recurrence and the malignant transformation rates of OPMDs treated with CO2 laser at the University Hospital of Bordeaux, in France, from 2010 to 2014, and identified associated factors with recurrence or malignant transformation.  They conducted a retrospective study in patients with a minimum follow-up of 12 months.  Collected variables included characteristics of the patients (gender, age, alcohol and tobacco consumption, previous diagnosis of graft-versus-host disease [GVHD], previous treatments for OPMD or for upper aero-digestive tract cancers and human immunodeficiency virus [HIV] infection), characteristics of the lesions (form, color, size, location, degree of dysplasia), laser treatment outcome (complications, recurrence, malignant transformation).  A total of 25 patients were included; mean follow-up was 28.9 months.  Recurrence was observed in 11 patients (44 %).  Annual recurrence rate was 18.3 % and annual malignant transformation rate was 1.7 %.  Hyperplasia without dysplasia was the only factor found to be statistically associated with recurrence.  The authors concluded that these findings suggested that OMPDs treated by CO2 laser vaporization had high recurrence rates, particularly those presenting hyperplasia.  They stated that a standardized definition of recurrence would be necessary for inter-study comparisons; long-term follow-up is recommended in order to detect and treat squamous cell carcinoma in its early stages.  Moreover, these investigators stated that RCTs should be used to evaluate the outcome of different treatment methods and multi-center studies could increase the power of statistical analyses. 

The authors stated that this study had several drawbacks.  First, this was a retrospective study.  It was based on complete records from the archives of the University Hospital of Bordeaux.  Second, the sample size was small (n = 25) but similar to that reported in some studies with CO2 laser vaporization.  This was due to the characteristics of the studied lesions themselves which were rare (less than 5 %) and required further follow-up to observe a potential recurrence or malignant transformation.  These researchers had a small sample size despite a 4-year screening period, providing a small power to identify associated factors, but on the other hand, they had data of good quality from a homogeneous sample (severe dysplasia excluded, all treated by CO2 laser by the same surgeon) followed-up at least 12 months as indicated by Brouns et al.  These lesions should become even rarer as the prevalence of tobacco smoking is declining worldwide, pointing out the need for future systematic reviews and meta-analyses, in which this study can contribute, and collaborative multi-center studies.

Vaginal Atrophy and Dysparenuria (MonaLisa Touch Laser)

Tschanz et al (2001) observed 3 cases of vulvodynia after CO2 laser (pulse or scan) treatment of condylomata acuminata (n = 1) or bowenoid papulosis (n = 2) of the female genital mucosa. Laser treatment was associated with a considerable delay in healing (3 to 4 months) and chronic pain.  The histology of the treated areas showed a scar tissue and severe mucosal atrophy.  The occurrence of painful scars following CO2 laser treatment could be related to an inadequate laser technique considering the morphology of the vagina.

In a pilot study, Salvatore et al (2014) evaluated the feasibility and effectiveness of fractional CO2 laser in the treatment of vulvo-vaginal atrophy (VVA) in post-menopausal women.  VVA symptoms were assessed before and after 3 applications of laser over 12 weeks in 50 women (aged 59.6 ± 5.8 years) dissatisfied with previous local estrogen therapies.  Subjective (visual analog scale) and objective (Vaginal Health Index Score, VHIS) measures were used during the study period to assess VVA.  Quality of life was measured by using the SF-12.  A subjective scale to evaluate the degree of pain related to the laser application and the degree of difficulty to perform the laser procedure was used.  Fractional CO2 laser treatment was effective to improve VVA symptoms (vaginal dryness, vaginal burning, vaginal itching, dyspareunia, dysuria; p < 0.001) at 12-week follow-up, as well as the VHIS (13.1 ± 2.5 at baseline versus 23.1 ± 1.9; p < 0.001).  Both physical and mental scores of quality of life were significantly improved in comparison with baseline (p < 0.001).  Satisfaction with the laser procedure was reported by 42 women (84 %) and a minimal discomfort was experienced at the 1st laser application, mainly because of the insertion and the movements of the probe.  Finally, the technique was very easy to perform in all women starting from the 2nd application at week 4 and no adverse events were recorded during the study period.  The authors concluded that a 12-week treatment with the fractional CO2 laser was feasible and induced a significant improvement of VVA symptoms by ameliorating vaginal health in postmenopausal women.  They stated that further controlled studies should be performed to confirm the present data and to assess the long-term effects of the laser procedure on vaginal tissues.

In a prospective study, Salvatore et al (2015) examined the effects of fractional micro-ablative CO2 laser on sexual function and overall satisfaction with sexual life in post-menopausal women with VVA. A total of 77 post-menopausal women (mean age of 60.6 ± 6.2 years) were treated for VVA symptoms with the fractional micro-ablative CO2 laser system (SmartXide(2) V(2)LR, MonaLisa Touch, DEKA, Florence, Italy).  Sexual function and quality of life were evaluated with the Female Sexual Function Index (FSFI) and the Short Form 12 (SF-12), respectively, both at baseline and at 12-week follow-up.  A 10-mm visual analog scale was used to measure the overall satisfaction with sexual life and the intensity of VVA symptoms (vaginal burning, vaginal itching, vaginal dryness, dyspareunia and dysuria) before and after the study period.  These researchers observed a significant improvement in the total score and the scores in each specific domain of the FSFI at 12-week follow-up compared to baseline (p < 0.001).  After concluding the laser treatment, the overall satisfaction with sexual life significantly improved (p < 0.001).  Seventeen (85 %) out of 20 (26 %) women, not sexually active because of VVA severity at baseline, regained a normal sexual life at the 12-week follow-up.  Finally, these investigators also found a significant improvement in each VVA symptom (p < 0.001) and in quality-of-life evaluation, both for the scores in the physical (p = 0.013) and mental (p = 0.002) domains.  The authors concluded that fractional micro-ablative CO2 laser treatment is associated with a significant improvement of sexual function and satisfaction with sexual life in post-menopausal women with VVA symptoms. 

There is currently insufficient evidence to support the use of MonaLisa Touch Laser (fractional CO2 laser) for gynecologic health (e.g., vaginal atrophy and dysparenuria).

Arunkalaivanan and colleagues (2017) noted that interest in laser therapy as a non-hormonal option for the treatment of genitourinary syndrome of menopause (GSM) has increased.  These investigators conducted a systematic review of the use of laser therapy for the relief of GSM symptoms.  A total of 6 electronic databases were searched and conference abstracts were searched manually from the introduction of laser therapy to the present date.  The keywords used were: "genitourinary syndrome", "vulvovaginal atrophy", "postmenopausal symptoms", "laser therapy" and "fractional laser treatment".  Of the 165 articles identified in the search, none was a RCT.  As a result, these researchers included 3 observational studies without a control group and 1 case-control study that met the inclusion criteria.  The total number of women included in the 4 studies was 220.  The collated data suggested that laser therapy may be valuable as a non-hormonal therapeutic modality in the management of GSM.  Moreover, they stated that higher quality of evidence from RCTs is needed to establish the efficacy of laser treatment in the management of GSM.

An UpToDate review on “Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)” (Bachmann and Santen, 2018) states that “Laser treatment is available for potential treatment of vulvovaginal atrophy with/without urinary incontinence.  The laser technologies deliver either fractional CO2 laser energy, and some systems use non-ablative photothermal Erbium:YAG-laser to the vaginal wall tissue.  Laser therapy typically consists of 3 laser treatment sessions over a specified time period (usually 1 session every 4 to 6 weeks) … Laser devices have not been approved by the US Food and Administration for the treatment of vulvovaginal atrophy.  The American College of Obstetricians and Gynecologists has advised that: Although initial observational data indicate potential utility, additional data from randomized trials are needed to further assess the efficacy and safety of this procedure in treating vulvovaginal atrophy, particularly for long-term benefit; and obstetrician-gynecologists should be cognizant of the evidence regarding innovative practices and should be wary of adopting new or innovative approaches on the basis of promotions or marketing.  Additional large clinical trials are actively recruiting subjects”.

Fractional CO2 Laser for Burn Scars

Connolly and colleagues (2014) stated that fractional CO2 laser has recently emerged as a promising therapeutic modality to improve the texture and appearance of burn scars.  An issue in many burn scars is persistent erythema, which traditionally has been treated with vascular lasers.  Interestingly, fractional CO2 lasers have been shown to improve the appearance of burn scars, including erythema, but no mechanism has been proposed for this change.  These researchers evaluated the histopathological changes in vasculature in burn scars treated with fractionated CO2 laser, and described the mechanism behind reduced erythema following treatment.  This was an uncontrolled, prospective study of 10 patients with mature burn scars, from a clinical and histological perspective.  Biopsy specimens were obtained before and 2 months after 3 treatment sessions.  Anti-CD31 immuno-staining was performed to highlight vascular patterns in biopsy specimens.  In histological analysis, an increase in vascular density, particularly of small caliber vessels, was seen following treatment, with an 82.6 % average increase in vasculature (p = 0.028).  This increase in vascularity correlated with a decrease in clinical erythema and vascularity scores, measured using the Vancouver Scar Scale.  The authors concluded that mature hypertrophic burn scars treated with a fractional CO2 laser showed a statistically significant increase in vascular density in the superficial dermis; but a non-statistical decrease in clinically perceived erythema and improvement of overall appearance was observed.

International guideline recommendations on scar management (Gold et al, 2014) stated that “ablative and non-ablative fractional lasers are focus of much current research and that the evidence is generally favorable in scientific literature for preventative and treatment applications”.  Other guidelines on scar management have reached similar conclusions about the investigational nature of CO2 laser for burn scars (Monstrey et al, 2014).

Anderson et al (2014) noted that despite expert wound care and assiduous management with traditional therapy, poor cosmetic outcomes, restricted motion, and symptoms such as pain and itch are a pervasive problem of disfiguring and debilitating scars.  The advent of ablative fractional photo-thermolysis within the last 10 years and its application to the treatment of traumatic scars represents a breakthrough in the restoration of function and cosmetic appearance for injured patients, but the procedure is not widely used.  In a consensus report, these investigators provided a synthesis of their current clinical experience and available literature regarding the laser treatment of traumatic scars with an emphasis on fractional re-surfacing.  A total of 8 independent, self-selected academic and military dermatologists and plastic surgeons with extensive experience in the use of lasers for scar treatment assembled for a 2-day ad-hoc meeting on January 19 and 20, 2012.  Consensus was based largely on expert opinion; however, relevant literature was cited where it exists.  After consensus was appraised, these researchers drafted the manuscript in sections during the course of several months.  The draft was then circulated among all panel members for final review and comment.  The consensus was that laser treatment, especially ablative fractional re-surfacing, deserves a prominent role in future scar treatment paradigms, with the possible inclusion of early intervention for contracture avoidance and assistance with wound healing.  The authors concluded that laser scar therapy, especially fractional ablative laser re-surfacing, represents a promising and vastly underused tool in the multi-disciplinary treatment of traumatic scars.  Changes to existing scar treatment paradigms should include extensive integration of fractional re-surfacing and other combination therapies guided by future research.

In a controlled study, El-Zawahry and associates (2015) evaluated and correlated the clinical and histopathological effects of fractional CO2 laser on thermal burns.  A total of 15 patients (11 with hypertrophic and 4 with keloidal scars) received 3 CO2 fractional laser sessions every 4 to 6 weeks; 50 % of the scar was untreated as a control.  Clinical evaluation by Vancouver, PSOAS scores, and photography before, monthly, and 3 months after the last laser session was performed; 10 patients were evaluated histopathologically by standard H&E, Masson trichrome, and Elastica von Gieson special stains.  Hypertrophic scars (HTSs) showed textural improvement and a significant decrease of Vancouver, POSAS observer, and patient scores by the end of follow-up period in the laser-treated area (p = 0.011, 0.017 and 0.018, respectively) unlike keloidal scars.  Histopathology revealed significant decrease in scar thickness in HTSs only (p < 0.001) as well as a significant decrease in collagen bundle thickness and density in the upper dermis in both types of scars.  The authors concluded that fractional CO2 laser is a possible safe and effective modality for the treatment of hypertrophic burn scars with improvement achieved both clinically and histopathologically.  These preliminary findings from a small study (n = 15) need to be validated by well-designed studies.

Levi and co-workers (2016) described their results and patient-reported outcomes with the use of fractional CO2 laser for the treatment of burn-related scarring.  These researchers performed a retrospective study of all patients who underwent CO2 laser procedures for treatment of symptomatic burn scars and skin grafts.  Burn injury and laser treatment demographics, as well as complications, were reported.  A questionnaire was administered to all patients and included patient-reported outcome measures aimed at understanding the patient experience and their subjective response to treatment.  A total of 387 CO2 laser procedures were performed on 131 patients for the treatment of symptomatic burn scars and skin grafts between October 1, 2011, and May 1, 2014 (average of 2.95 procedures/patient; range of 1 to 11).  Average time between injury and first laser was 597.35 days (range of 60 to 13,475).  Average time between laser treatments (when multiple) was 117.73 days (range of 22 to 514).  There were no infections requiring treatment with oral antibiotics.  Overall patient satisfaction with laser therapy was 96.7 %.  Patients reported reductions in neuropathic pain, tightness (contracture), and pruritus (54.0, 50.6, and 49.0 %, respectively).  The authors concluded that fractional photothermolysis utilizing the CO2 laser is a safe and effective modality for the treatment of symptomatic burn scars, donor sites, and skin grafts.  Patient satisfaction with this procedure is high, and complications were low.  Significant improvements in scar appearance, pliability, tightness, neuropathic pain, and pruritus were commonly reported.  The major drawbacks were its retrospective design and that it was a single-center study.

The main drawback of this study was that these investigators included only the patients with hypertrophic scars, not all the children with burn scars.  The authors noted that they knew that the keloids treatment results would be worse, and if they mixed all the scars, result would not be so great.  The other drawback was excluding patients with parents who do not pay enough attention to their children: in order to achieve good long-term outcomes, strict control of the healing process after the procedure is necessary.  The healing process takes about 10 to 14 days maximum; therefore, the exclusion criteria rule out the patients with poor social and living conditions: parents who do not care about sufficient assessment, parents who did not respond to previous recommendations, missed check-outs, or do not pay enough attention to hygiene process for their children.  These investigators stated that laser therapy in the treatment of hypertrophic scars is still at a very early stage of development.  There is no guidance on which type of laser or energy dose should be used or the frequency of repeated treatments.  This is connected with the high volatility of scars, their different location, and morphology.  They stated that it appeared that the further development of technologies will allow reduction of the number of complications and increase the effectiveness of treatment; the results obtained in this work are very promising but of course need further evaluation.

Furthermore, an UpToDate review on “Management of keloid and hypertrophic scars following burn injuries” (Gauglitz, 2017) states that “Fractional lasers might play a promising role in the treatment of widespread burn scars.  Improvements in both clinical and structural features of burn scars have been reported after fractional CO2 laser procedures.  However, more in-depth studies are needed to identify the underlying mode of action and clinical treatment regimens before definite recommendations for treatment protocols can be made”.

In an uncontrolled, open-label, clinical trial, El-Hoshy and colleagues (2017) evaluated the efficacy of fractional CO2 laser use in the treatment of mature burn scars.  A total of 20 patients with mature burn scars were included in the study.  A total of 3 fractional CO2 laser sessions were given, 4 to 8 weeks apart.  Primary outcome was measured using 2 scar scales, the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale.  Secondary outcomes included evaluation of collagen and elastic fibers using routine hematoxylin and eosin, Masson's trichrome, and orcein stains.  Outcomes were measured 2 months after the last laser session.  Both Vancouver Scar Scale and Patient and Observer Scar Assessment Scale showed significant reduction following treatment (p < 0.001).  Scar relief and pliability improved most followed by vascularity.  Pigmentation improved the least.  Percent improvement in Patient and Observer Scar Assessment Scale patients' overall assessment was 44.44 %.  The pattern and arrangement of collagen and elastic fibers showed significant improvement (p < 0.001, p = 0.001, respectively), together with significant improvement in their amounts (p = 0.020, p < 0.001, respectively).  No significant correlation existed between clinical and histopathological/histochemical scores.  Side effects and complications were mild and tolerable.  The authors concluded that fractional CO2 laser can be a safe and effective modality in the treatment of post-burn scars.  It achieved significant change in the opinion of the patients about their scar appearance.  Moreover, they noted that limitations of this study included its small sample size (n = 20) and the relatively short follow-up period (2 months).

Willows et al (2017) stated that burn scars are associated with significant morbidity ranging from contractures, pruritus, and disfigurement to psychosocial impairment.  Traditional therapies include silicone gel, compression garments, corticosteroid injections, massage therapy, and surgical procedures; however, newer and advanced therapies for the treatment of burn scars have been developed.  Lasers, specifically ablative fractional lasers, show potential for the treatment of burn scars.  These researchers carried out MeSH and keyword searches of the PubMed, Medline and Embase databases for relevant articles; and they were read in full for the compilation of this review.  A total of 51 relevant observational studies, clinical trials, and systematic reviews published in English from 2006 to 2016 were reviewed and summarized.  The authors concluded that laser therapy was effective for the treatment of burn scar appearance, including measures such as pigmentation, vascularity, pliability, and thickness.  Ablative fractional laser therapy, in particular, showed significant potential for the release of contractures allowing for improved range of motion of affected joints.  Patients may benefit from the use of lasers in the treatment of burn scars, and the safety profile of lasers allowed the benefits of treatment to outweigh the risks.  Laser therapy should be included in burn scar treatment protocols as an adjuvant therapy to traditional interventions.

Miletta et al (2019) stated that fractional CO2 laser treatment has been reported to improve burn scars, with increasing clinical use despite a paucity of controlled, prospective clinical studies using objective measures of improvement.  In a prospective, open-label, site-controlled, multi-center study, these researchers determined objective and subjective changes in mature hypertrophic burn scars treated with a fractional ablative CO2 laser.  This trial was carried out from 2013 to 2016.  Objective and patient-reported outcome measures were documented at baseline, at each monthly laser treatment, and 6 months after treatment.  Objective measurements included mechanical skin torque to measure viscoelastic properties; ultrasonic (US) imaging to measure scar thickness; and reflectometry to measure erythema and pigmentation.  Subjective measures included health-related QOL (HR-QOL), patient and investigator scar assessment scales, and blinded scoring of before and after photographs.  Subjects aged 11 years or older with hypertrophic burn scars were recruited.  Each subject received 3 monthly treatment sessions with an ablative fractionated CO2 laser.  A total of 29 subjects were enrolled, of whom 26 received at least 1 fractional CO2 laser treatment and 22 received 3 treatments.  Mean age of those completing all 3 treatments was 28 years.  Statistically significant objective improvements in elastic stretch (p < 0.01), elastic recovery (p < 0.01), extensibility (p < 0.01), and thickness (p < 0.01) were noted.  Patient- and physician-reported scar appearance and pain/pruritus were significantly improved (p < 0.01).  There was no regression of improvement for at least 6 months after treatment.  The authors concluded that fractional ablative laser treatment provided significant, sustained improvement of elasticity, thickness, appearance, and symptoms of mature hypertrophic burn scars.

Daoud et al (2019) noted that scar rehabilitation is a complex process that incorporates medical, surgical, and physical therapeutic measures to best restore function and visual normalcy.  Lasers have emerged as essential tools in the management of scars, with devices available to address scar size, dyschromia, and contour irregularities.  As different lasers treat these different features, multi-laser, same session therapeutic approaches may offer a more comprehensive approach to scar revision.  In an institutional review board (IRB)-approved RCT, these researchers examined the effect of a combinatorial, same session treatment with intense pulsed light (IPL) and fractional ablative CO2 as compared to single laser treatment with fractional ablative CO2 laser alone or control in the treatment of mature hypertrophic scars.  This study enrolled 23 healthy adults with large (greater than 100 cm2) hypertrophic scars who were randomized to 1 of 3 treatment arms: IPL and CO2 ablative fractional laser (AFL); CO2-AFL alone; and control (no laser treatment).  Subjects underwent a total of 4 treatment sessions at 6- to 8-week intervals with follow-up visits at 1, 3, and 6 months after the last treatment session.  Primary endpoints included blinded scoring of before and after photographs via the Manchester Scar Scale (MSS); secondary endpoints included the Patient-Observer Scar Assessment Scale (POSAS).  As compared to control and CO2-AFL laser alone, the combination of CO2-AFL and IPL demonstrated statistically significant improvement across a greater number of scar domains, as assessed by the MSS; 100 % of subjects in both treatment groups showed a statistically significant decrease in the POSAS scale after the series of 4 treatment sessions.  No adverse events (AEs) were reported.  The authors concluded that treatment with combined IPL and CO2-AFL demonstrated higher average improvements across the majority of assessed scar domains, as compared to both control and CO2 laser alone.  The difference was not statistically significant in overall MSS score as expected due to the role of CO2 as the main source of improvement.  However, only the combination group had statistically significant improvement in both color and texture.  These findings supported the assertion that a multi-photo-thermolytic approach with combined IPL and CO2-AFL could have a positive impact on the treatment of hypertrophic scars by using multiple wavelengths to maximize laser-skin interactions in targeting the different chromophores expressed in scar tissue.

Patel et al (2019) stated that CO2-AFL therapy has not been widely adopted in pediatric burn care given limited outcomes literature and no established guidelines on laser treatment protocols.  These researchers presented their experience to further examine the clinical role of CO2-AFL therapy for pediatric hypertrophic burn scars.  These investigators carried out a prospective cohort study of pediatric burn patients undergoing CO2-AFL treatment of hypertrophic, symptomatic burn scars at a tertiary care regional burn center during a 2-year period.  Scars were examined before each treatment using the POSAS.  They treated 49 pediatric patients for a total of 180 laser sessions.  Burn severity was full thickness (63.6 %) or deep partial thickness (47.7 %).  Observer-rated POSAS scores revealed statistically significant improvements in pigment, thickness, relief, pliability, and surface area after 1 treatment with continued improvement until the last laser session.  Patient-rated POSAS revealed statistically significant improvements in color, stiffness, thickness, and irregularity after laser treatments.  Total POSAS improved from 89.6 ± 17.5 to 76.6 ± 16.8 (p < 0.0001) after 1 treatment with further improvement to 69.2 ± 14.9 (p < 0.0001) at the final laser session.  These researchers found convincing evidence that CO2-AFL therapy improved hypertrophic burn scars on both patient- and observer-rated scales confirming statistical and clinical significance to both providers and families.  The authors concluded that these findings demonstrated that CO2-AFL could improve hypertrophic burn scars in pediatric patients providing a lower risk alternative to invasive therapies and a more immediate, effective alternative to more conservative scar treatments.

Lei et al (2020) examined the effect of combined application of PDL and ultra-pulsed fractional carbon dioxide laser (UFCL) in the treatment of pediatric large burn scars at early stage.  A total of 120 pediatric patients with large burn scars at early stage conforming to the study criteria were admitted to the People's Hospital of Hunan Province from January 2016 to December 2019.  Their data were retrospectively analyzed by the method of single case-control study.  There were 78 males and 42 females with age of 4.2 ± 0.8 years and scar area of 100.3 ± 0.7 cm(2).  PDL combined with UFCL was used for the first time.  The treatment interval of PDL was 1 month and the treatment interval of UFCL was 3 months.  The total treatment cycle was 6 months, with 2 PDL treatments alone and 2 combined treatments.  Before the 1st combined treatment and 6 months after 2 combined treatments, the curative effect was assessed using POSAS by doctors and family members of pediatric patients.  Satisfaction degrees of the family members of pediatric patients were recorded, and the overall satisfaction rate was calculated 6 months after 2 combined treatments.  The adverse effects during the whole treatment course were recorded.  Data were statistically analyzed with paired t-test.  Six months after 2 combined treatments, the scores of pediatric patients' scar vascularity, pigment, thickness, relief, pliability, surface area, and overall valuation in POSAS by doctors and the scores of pain, itch, color, stiffness, thickness, irregularity, and overall valuation in POSAS by family members of pediatric patients were all significantly lower than those before the first combined treatment (t = 16.6, 16.0, 16.9, 14.9, 20.8, 29.3, 30.7, 20.4, 29.3, 18.1, 27.9, 25.8, 20.8, 45.3, p < 0.01).  The overall evaluation scores by doctors were 8.1 ± 0.8 and 2.7 ± 0.6 points, and the overall evaluation scores by family members of pediatric patients were 8.2 ± 0.8 and 2.4 ± 0.5 points, respectively, before the 1st combined treatment and 6 months after 2 combined treatments.  Six months after 2 combined treatments, 110 (92 %) family members of pediatric patients were very satisfied with the curative effect, 6 (5 %) family members of pediatric patients were satisfied, and 4 (3 %) family members of pediatric patients were relatively satisfied with no unsatisfied reported.  The overall satisfaction rate was 97 % (116/120).  During the treatment, pruritus and rash appeared in 5 pediatric patients 3 to 4 days after the 1st treatment; pigmentation appeared in 3 pediatric patients 3 weeks after the 1st treatment; pruritus and vesicle appeared in 1 patient 1 week after the 3rd treatment.  No adverse effects such as aggravated scar or infection were observed on the wounds.  The authors concluded that in treating pediatric large burn scars at early stage, PDL combined with UFCL has demonstrated significant effect with short treatment cycle, few adverse effects.  The combined treatment could alleviate symptoms and improve the QOL of pediatric patients; and is worthy to be popularized and used in clinic.

Tawfic et al (2020) stated that fractional CO2 laser has been shown effective in improving pigmentation, pruritus, and tightness of hypertrophic burn scars; however, there is no consensus on the optimal treatment parameters.  These researchers compared the effectiveness of different densities of fractional CO2 laser in the treatment of mature hypertrophic burn scars.  The study included 25 patients, each with 3 or more mature hypertrophic burn scars.  Scars were randomly assigned to treatment with low-, medium-, and high-density fractional CO2 laser.  Each scar received 3 sessions of laser at 1-month interval.  The degree of improvement was assessed clinically using VSS and POSAS scores, and histologically via evaluation of collagen (Masson's Trichrome stain) before and 1 month after end of therapy.  High-density parameters showed significant higher improvement in VSS and POSAS assessment scores (p < 0.001).  Pliability and relief were the most improved parameters.  Histopathological evaluation revealed a significant drop in the mean area percent of collagen in the 3 used parameters, with highest improvement with high-density laser treatment (p < 0.001).  The authors concluded that high-density fractional CO2 laser treatment provided more improvement in burn scars both clinically and histopathologically.

In a retrospective study, Meynkohn et al (2020) examined if CO2-AFL treatment could positively influence facial scarring and QOL while improving the aesthetic appearance.  Patients with facial scars who had received CO2-AFL treatment between May 2019 and May 2020 were included in this trial.  The post-interventional course and patient and/or observer reported outcomes were inquired before and 3 months after treatment.  Primary outcomes were changes in the POSAS and QOL (Short Form (SF)-36).  Furthermore, 2 independent examiners examined the aesthetic outcome by comparing initial scarring with the post-intervention results using photographs.  A total of 16 patients with facial scars were included.  Most of the scars were caused by burns (43.8 %) or trauma (31.3 %).  The post-interventional course was uneventful.  Overall POSAS scores improved decisively for both observers (n = 2) and patients (n = 16) (p < 0.001 and p < 0.001).  Furthermore, there was an improvement in QOL with an increase in emotional well-being (p = 0.043) and social functioning (p = 0.01).  In addition, the aesthetic outcome was significantly enhanced (p = 0.001) after treatment.  The authors concluded that CO2-AFL offered a safe and effective treatment for disfiguring facial scars. 

Godara et al (2020) noted that surgical correction of scars may not be an ideal solution in all cases and hence it is desirable to have a non-surgical option available.  Autologous platelet-rich plasma (PRP) and fractional CO2 laser (FCL) offer an alternative treatment modality.  In a prospective, randomized, observer-blinded, comparative study, these researchers compared the safety and effectiveness of FCL and intra-dermal PRP with FCL in the management of post-burn and post-traumatic scars.  This trial was conducted at a hospital skin center from October 2016 to September 2018.  A total of 67 patients with scars were randomly divided into 2 groups: Group I was treated with 4 sessions of monthly FCL; and Group II was treated with 4 sessions of PRP and FCL.  Patients were examined using POSAS at baseline and 4 weeks after each session.  For continuous variables, the summary statistics of mean ± standard deviation (SD) was used; for categorical data, number and percentage were used.  Chi-square (χ2) test was used for association between 2 categorical variables; and p < 0.05 was considered to be statistically significant; 30 cases in each group completed the study.  There was a significant improvement in the total score of POSAS (p < 0.001) in both groups, but the final difference between the 2 groups was not statistically significant (p = 0.793 and p = 0.278, respectively).  The authors concluded that fractional CO2 laser resulted in significant improvement in scar appearance; however, PRP in combination with FCL offered no additional advantage.

Seago et al (2020) stated that there is currently intense multi-disciplinary interest and a maturing body of literature regarding laser treatments for traumatic scars; however, international treatment guidelines and reimbursement schemes have not yet caught up with current knowledge and practice in many centers.  These investigators examined the potential of laser techniques, offered recommendations for safe and effective treatment, and promoted wider patient access guided by future high-quality research.  An international panel of 26 dermatologists and plastic and reconstructive surgeons from 13 different countries with a variety of practice backgrounds was self-assembled to develop updated consensus recommendations for the laser treatment of traumatic scars.  A 3-step modified Delphi method took place between March 2018 and March 2019 consisting of 2 rounds of e-mailed questionnaires and supplementary face-to-face meetings.  The panel members approved the final manuscript via e-mail correspondence, and the threshold for consensus was at least 80 % concurrence among the panel members.  The manuscript included extensive detailed discussion regarding a variety of laser platforms commonly used for traumatic scar management such as vascular lasers and ablative and non-ablative fractional lasers, special considerations such as coding and laser treatments in skin of color, and 25 summary consensus recommendations.  The authors concluded that lasers are a 1st-line therapy in the management of traumatic scars and contractures, and patients without access to these treatments may not be receiving the best available care after injury.  Updated international treatment guidelines and reimbursement schemes, additional high-quality research, and patient access should reflect this status.

Klifto et al (2020) noted that hypertrophic scars often develop following burn-related injuries.  These scars can be cosmetically unappealing; moreover, associated symptoms of pruritus, pain and restricted range of motion (ROM) could impair a person's QOL.  Laser and light therapies offer a minimally invasive, low-risk approach to treatment, with a short post-operative recovery period.  As laser technology developed, studies have shown decreased scar thickness, neuropathic pain and need for surgical excision, as well as improved scar pigmentation, erythema, pliability, texture, height and pruritus.  The authors presented the evolution of laser therapy for hypertrophic burn scars, how different types of lasers work, indications, peri-operative considerations and guidelines for practice management.  They stated that PDL therapy and ablative fractional resurfacing (AFR) laser therapy are 2 types of lasers that have shown the greatest effectiveness when treating hypertrophic scars.

In a retrospective study, Tan et al (2021) examined the safety and effectiveness of ablative fractional CO2 laser treatments for hypertrophic burn scars and analyzed its safety and effectiveness in the early period within 3 months after injury.  This trial was carried out on 221 hypertrophic scar patients.  According to the time of the 1st laser treatment after injury, patients were divided into 5 subgroups, including less than 1 month, 1 to 3 months, 3 to 6 months, 6 to 12 months, and more than 12 months post-injury.  One month after the last laser treatment, the scars were assessed by photography, the VSS, durometry, and spectro-colorimetry.  Subjects included 118 males and 103 females; the average age was 33.6 years.  Fire/flame was the primary injury source; 36 % of the patients underwent at least 1 fractional CO2 laser treatment.  All the included patients, including those treated within 1 month after injury, had significantly decreased VSS scores after laser treatment.  These investigators also noted that hardness and redness scores were decreased after treatment for both scars treated within 3 months and those treated more than 12 months after injury.  Seepage (17.6 %), bleeding (22.2 %), and swelling (9.0 %) were the main AEs following laser treatment.  The authors concluded that the findings of this study demonstrated the safety and effectiveness of ablative fractional CO2 laser treatment applied to early stage burn scars.  The optimal time for laser application for patients who suffered burns can be within 1 month after injury.  Durometry and spectro-colorimetry were effective for evaluating scars as objective modalities.

Zhang et al (2021) examined the effectiveness of fractional CO2 laser for the treatment of burn scars.  These researchers carried out a literature search in electronic databases and studies were selected by following pre-determined eligibility criteria.  Random effect meta-analyses were performed to achieve the effect size of the changes (mean difference (MD) between post-treatment and pre-treatment values) in selected scar assessment scale scores and other important outcome measures.  A total of 14 studies were included.  Treatment of burn scars with fractional CO2 laser significantly improved VSS (MD -3.01 [95 % CI: -3.79 to -2.22]; p ˂ 0.00001), POSAS-Patient (MD -14.38; 95 % CI: -17.62 to -11.13; p ˂ .00001, POSAS-Observer (MD -8.81; 95 % CI: -11.60 to -6.02; p ˂ 0.00001; and Scar Assessment Scale (MD 1.64; 95 % CI: 0.49 to 2.78; p = 0.005) scores especially with regards to pigmentation, vascularity, pliability, and height of scar.  Pain and pruritis also improved with this treatment.  Scar thickness measured with US decreased non-significantly (MD -0.48; 95 % CI: -1.04 to 0.09; p = 0.1) whereas cutometer measures, R0 (scar firmness) and R2 (scar elasticity) did not change meaningfully.  The authors concluded that fractional CO2 laser therapy is a valuable tool for the treatment of burn scars that has potential for reducing scar severity.

Sitohang et al (2022) stated that hypertrophic scars present collagen deposition and an abnormal extracellular matrix that cause abnormal shape changes and limit normal movement.  Although fractional CO2 laser therapy has provided promising evidence, the improvement of scarring has not been thoroughly reviewed.  These investigators carried out a systematic review of prospective, randomized studies collected from PubMed, Medline, Embase, Cochrane and Scopus databases on March 15, 2020 in accordance with the PRISMA-P statement.  Types and duration of fractional CO2 laser used in this study along with the comparative modalities were recorded in this review.  Treatment effectiveness was evaluated as the primary outcome; AEs and patient satisfaction were assessed as the secondary outcome.  A total of 5 prospective, randomized studies were included in this systematic review.  All studies included showed a consistent result with a conclusion that fractional CO2 laser treatment showed statistically significant improvement for various scar scoring methods.  Combination with other modalities may yield better results in some studies with the risk of more severe AEs.  Temporary side effects such as itching or burning sensation, erythema and edema were observed; but appeared to be minimal and well-tolerated.  Overall, patients reported significant improvement in QOL.  Some of the studies were uncontrolled with relatively short-term follow-up.  The authors concluded that this evidence suggested that fractional CO2 laser treatment is effective for improving the clinical appearance of hypertrophic scars with a good safety profile.

Furthermore, an UpToDate review on “Hypertrophic scarring and keloids following burn injuries” (Gauglitz, 2022) states that “For immature burn scar, minor burn keloid, or erythematous hypertrophic burn scar, we suggest intralesional injections with triamcinolone acetonide and silicone sheeting or gel as the first line of management (Grade 2C).  Pressure dressings can be applied for approximately 3 weeks to limit progression.  For widespread hypertrophic burn scars without associated tension, we suggest treatment with silicone sheeting or gel, or onion extract gel, and pressure therapy (Grade 2C).  For widespread hypertrophic burn scars associated with tension that limit function or cause contractures, we suggest surgical scar release and scar excision/revision with adjunctive use of silicone sheeting or gel, or onion extract gel, and pressure therapy (Grade 2C).  For patients who are not responsive to therapy, we use ablative fractional laser therapy”.

Fractional CO2 Laser for Morphea/Localized Scleroderma

Morphea is a rare fibrosing skin disorder that occurs as a result of abnormal homogenized collagen synthesis. Jacoby (2017) noted that ablative fractional laser therapy has been shown to be effective in a few patients with morphea (localized scleroderma) (citing Kineston, et al., 2011) 

Shalaby and colleagues (2016) evaluated the effectiveness of fractional CO2 laser as a new modality for the treatment of localized scleroderma and compared its results with the well-established method of UVA-1 phototherapy.  A total of 17 patients with plaque and linear morphea were included in this parallel intra-individual comparative RCT.  Each with 2 comparable morphea lesions that were randomly assigned to either 30 sessions of low-dose (30 J/cm2) UVA-1 phototherapy (340 to 400 nm) or 3 sessions of fractional CO2 laser (10,600 nm-power 25 W).  The response to therapy was then evaluated clinically and histopathologically via validated scoring systems.  Immunohistochemical analysis of TGF-ß1 and MMP1 was done.  Patient satisfaction was also assessed.  Wilcoxon signed rank test for paired (matched) samples and Spearman rank correlation equation were used as indicated.  Comparing the 2 groups, there was an obvious improvement with fractional CO2 laser that was superior to that of low-dose UVA-1 phototherapy.  Statistically, there was a significant difference in the clinical scores (p = 0.001), collagen homogenization scores (p = 0.012), and patient satisfaction scores (p = 0.001).  The authors concluded that fractional CO2 laser is a promising treatment modality for cases of localized morphea.

Fractional CO2 Laser for Keloids

Annabathula and co-workers (2017) evaluated the efficacy of fractional CO2 laser, long pulse Nd:YAG laser and PDL in the management of keloids.  A total of 15 patients with keloids were treated by fractional CO2 laser, followed by PDL and long pulse Nd:YAG laser at monthly intervals; 4 patients discontinued the study and were lost for follow-up.  Photographs were taken at the beginning of the treatment and at the end of 5 sessions.  Clinical improvement was analyzed based on a visual analog scale (VAS) graded by 3 blinded observers after assessing the clinical photographs for the improvement in size, color and aesthetic impression.  Of the 11 patients, 1 patient had excellent improvement, 1 patient had good improvement, 4 patients had moderate improvement, 2 patients had mild improvement and 3 had no improvement.  The authors concluded that lasers may have a synergistic effect when combined with other modalities of treatment; but cannot be used as monotherapy in the treatment of keloids.  The drawbacks of this study were its small sample size (n = 15) and the limited number of laser sessions (n = 5).

Fractional CO2 Laser for Vulvovaginal Atrophy Symptoms and Vaginal Rejuvenation in Peri-Menopausal Women

Arroyo (2017) examined a novel fractional CO2 laser for treatment of symptoms associated with VVA in peri-menopausal women.  The study included 21 peri-menopausal women (mean age of  45 ± 7 years) treated 3 times by CO2 laser resurfacing and coagulation of the vaginal canal tissue and mucosal tissue of the introitus.  Vaginal health index (VHI) scores were computed by the investigator at baseline and follow-ups.  Subjects reported on sexual function, satisfaction, and improvement with treatment.  A VAS was used to measure discomfort with treatment.  Vaginal health and subject assessment of vaginal symptoms improved with successive treatments.  At 12 weeks following the 3rd treatment, 82 % of the patients showed a statistically significant improvement in VHI (p < 0.05).  Additionally, 81 % of subjects reported improvement in sexual gratification, 94 % reported improvement in vaginal rejuvenation, and 100 % reported satisfaction with treatment.  VHI improvement remained significant at 6 to 8 months after treatments (p < 0.01).  Most patients (97 %) reported no to mild discomfort with treatment.  Responses were mild and transient following treatment, with itching being the most commonly reported (20 %) side effect.  The authors concluded that fractional CO2 laser treatment was associated with improvement of vaginal health and amelioration of symptoms of VVA, resulting in improved sexual function in peri-menopausal women.  Treatment time was quick, and there was minimal discomfort associated with treatment.  Moreover, they stated that investigation of clinical outcome in a larger study population is needed; investigation of long-term clinical outcome, up to 12 months post-treatment, in a post-menopausal population is currently ongoing at a multi-center study in the USA.

Cruff and Khandwala (2021) noted that despite some prospective, case-series studies showing effectiveness of vaginal laser in the treatment of genitourinary syndrome of menopause (GSM), there is a paucity of placebo-controlled level I evidence.  In a parallel, randomized, double-blind, sham-controlled study, these researchers examined the effect of fractional CO2) laser therapy for the treatment of GSM-related dyspareunia against a sham comparator.  A total of 3 treatments were given 6 weeks apart, and subjects attended a 6-month visit from study start for primary (proportion improved) and secondary (VHI, VAS, modified global assessment, patient global impression of improvement [PGI-I], FSFI, DIVA, urinary distress inventory short-form [UDI-6]) assessments.  The primary endpoint was a 2-stage improvement in GSM-related dyspareunia from baseline to 6 months determined by a severity scale, and the proportion of subjects who achieved this were compared between groups.   A total of 30 subjects were randomized to laser (n = 14) or sham (n = 16).  In the treatment arm, 13 attended all treatments, and 1 attended at least 2 while in the sham arm, 14 attended all treatments, and 2 attended at least 2 treatments; 12 (86 %) in the treatment arm and 16 (100 %) in the sham arm attended the 6-month visit.  There were no differences in the proportion improved between treatments and controls (64 % versus 67 %, respectively, p = 1.000).  Both arms showed significant within-group improvements based on VHI and VAS, but not between groups.  Similar findings were observed on sexual impact questionnaires with improvements within both groups from baseline to 6 months but not by median differences between the groups at 6 months.  There were no AEs in either of the arms.  The authors concluded that this study was under-powered to draw conclusions regarding the effectiveness of fractional CO2 laser therapy in the treatment of GSM.  These researchers observed improvements in the sham-arm to suggest a possible placebo contribution.  These investigators stated that further well-powered research is needed to determine the effectiveness of fractional CO2 laser for the treatment of GSM, especially in light of a potential placebo effect.

Mension and colleagues (2022) stated that GSM can have a great impact on the QOL; and affects between 53.8 % and 90 % of post-menopausal women.  Available evidence suggests that vaginal laser therapy could be an effective treatment for GSM symptoms; however, its safety and effectiveness have not been established and international societies do not endorse its use.  Despite that, there has been an increase in the use of vaginal laser therapy globally over the past 10 years.  In a systematic review, these investigators examined the literature that evaluated the safety and effectiveness of vaginal laser therapy in the treatment of GSM.  They carried out a comprehensive literature search using Embase and PubMed to retrieve studies evaluating evidence for the safety and effectiveness of vaginal laser therapy for GSM or vulvo-vaginal atrophy up to June 2021.  A total of 64 studies were finally included in the review.  There were 10 controlled intervention studies, 7 observational cohort and cross-sectional studies and 47 before-after studies without a control group.  The authors concluded that vaginal laser appeared to improve scores on the VAS, FSFI and VHI in GSM over the short term; however, safety outcomes were under-reported and short-term.  These researchers stated that further well-designed clinical trials with sham-laser control groups and evaluating objective variables are needed to provide the best evidence on the effectiveness of vaginal laser for the treatment of GSM.

diVa Laser Vaginal Therapy

diVa laser vaginal therapy is supposedly a quick vaginal rejuvenation solution.  It is an FDA-cleared vaginal therapy system that utilizes the Hybrid Fractional Laser technology that sends ablative as well as non-ablative wavelengths to the affected region to encourage cellular activity to restore vaginal tissue and improve sexual health.  The 1st laser deeply resurfaces the layers of the vaginal wall, replacing it with brand new, healthy tissue.  The 2nd laser heats the layers of the tissue where collagen exists; 3 treatments are recommended, spaced 30 days apart. 

Siliquini and colleagues (2017) examined the effects of CO2 laser in the treatment of VVA in post-menopausal women; VVA was assessed in 87 post-menopausal women (mean age of 58.6 ± 6.9 years) before and after the treatment.  The protocol consisted of 3 monthly treatments and included the treatment of vulva.  Subjective measures included VAS both for vaginal dryness and dyspareunia; DIVA (day-by-day impact of vaginal aging); a questionnaire on treatment satisfaction and one about the degree of pain during the procedure.  Objective measures included VHI and vulvo-vaginal health index (VVHI).  Time-points of the study were at the screening visit (T0), at baseline (T1), at week 4 (T2), at week 8 (T3), after 3 months since the last laser application (T4), after 6 months (T5), after 9 months (T6), after 12 months (T7) and after 15 months (T8).  Treatment induced significant improvement in the VAS score.  After treatment, VHI and VVHI indicated no VVA and this improvement was long-lasting.  Multi-variate analysis showed that the time of follow-up was correlated with better VHI and VVHI (p < 0.001).  DIVA improved over time (p < 0.001).  The authors concluded that this study showed that CO2 laser treatment induced a significant and long-lasting improvement of symptoms.  These findings need to be validated by well-designed studies.

An UpToDate review on “Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)” (Bachmann and Santen, 2019) states that “Laser devices have not been approved by the US Food and Administration for the treatment of vulvovaginal atrophy.  The American College of Obstetricians and Gynecologists has advised that: (i) Although initial observational data indicate potential utility, additional data from randomized trials are needed to further assess the efficacy and safety of this procedure in treating vulvovaginal atrophy, particularly for long-term benefit; and (ii) Obstetrician-gynecologists should be cognizant of the evidence regarding innovative practices and should be wary of adopting new or innovative approaches on the basis of promotions or marketing.  Additional large clinical trials are actively recruiting subjects”.

Fractional Carbon Dioxide Laser for Actinic Keratoses

Song and colleagues (2015) noted that a relatively long incubation time is needed for photo-sensitizer absorption in conventional PDT for actinic keratosis (AK).  The use of ablative CO2 fractional lasers (AFXLs) to increase drug delivery could shorten the incubation time.  These researchers compared the efficacy between AFXL-assisted PDT with a short incubation time and conventional PDT for AK.  Patients with histopathologically confirmed facial AK were randomly divided into 2 groups.  The lesions were histopathologically classified into grades I-III.  In the AFXL-assisted PDT group, an ablative fractional laser was used for pre-treatment, prior to the application of MAL, with an incubation time of 90 mins.  Irradiation was performed with a 630-nm light-emitting diode.  In the conventional PDT group, the incubation time was 180 mins.  All the patients received 2 rounds of PDT at 2-week intervals and underwent clinical or histological evaluation at 10 weeks after the 1st PDT course.  A total of 22 patients underwent conventional PDT and 24 patients underwent AFXL-assisted PDT; 34 AKs were included in the conventional PDT group, and 35 AKs were included in the AFXL-assisted PDT group.  The clearance rate was 64.7 % in the conventional PDT and 71.4 % in the AFXL-assisted PDT group; no significant differences in the clearance rate were noted between the groups (p = 0.55).  The clearance rates for each grade also did not significantly differ between the 2 groups.  The authors concluded that the use of AFXL before PDT reduced the incubation time, but yielded similar treatment efficacy as compared to conventional PDT.

Steeb and associates (2019) noted that PDT is an effective intervention for AK and field cancerization; ablative fractional lasers may facilitate the delivery of photo-sensitizers and thereby improve the effects of PDT.  These researchers summarized the current evidence on the safety and efficacy of laser-assisted PDT.  They carried out a systematic literature research in Medline, Embase, and the Cochrane Central Register of Controlled Trials and hand-searched pertinent trial registers for eligible RCTs.  Results from individual studies were pooled by using a random-effects model.  The risk of bias was estimated with the Cochrane Risk of Bias Tool, and the quality of evidence of the outcomes was assessed with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.  Of 817 records initially identified, 7 RCTs were included in the qualitative analysis and 4 were included in the meta-analysis.  Laser-assisted PDT showed significantly higher clearance rates than did PDT monotherapy (risk ratio [RR], 1.33; 95 % CI: 1.24 to 1.42; I2 = 25 %; p < 0.01).  There was no difference in pain intensity between laser-assisted PDT and other interventions (mean difference [MD], 0.31; 95 % CI: -0.12 to 0.74; I2 = 0 %; p = 0.16).  The included studies showed a high risk of bias.  The authors concluded that laser-assisted PDT was more efficient; but not more painful than PDT or laser treatment only.  These researchers stated that the main drawback of this study was the clinical heterogeneity of included studies.

Furthermore, an UpToDate review on “Treatment of actinic keratosis” (Jorizzo, 2019) states that “Laser therapy -- Additional therapies that have been utilized for AKs include ablative laser resurfacing with carbon dioxide (CO2) and erbium:yttrium aluminum garnet (Er:YAG) lasers. A few uncontrolled studies have reported reductions in AKs following treatment with non-ablative fractional lasers; however, a 6-month follow-up with histologic evaluation performed in one of the studies revealed persistence of AKs after treatment”.

Laser Therapy for Aphthous Stomatitis

Amorim Dos Santos and colleagues (2020) examined the therapeutic effects of laser therapy on patients with recurrent aphthous stomatitis by evaluating evidences from previously published systematic reviews.  These investigators carried out an overview of systematic reviews based on PRISMA check-list.  Search strategies were developed and adapted for 6 different electronic databases and a gray literature search was also performed.  The methodology quality of the included systematic reviews was assessed by the Measurement Tool to Assess the Methodological Quality of Systematic Reviews 2 (AMSTAR 2).  After a 2-step selection, 5 systematic reviews were included.  Methodology quality was considered as a high risk of bias in 2 systematic reviews, while in the other 3 were graded as moderate.  The systematic reviews' conclusions demonstrated that all included systematics reviews showed positive effects of laser therapy for pain relief, and most of them demonstrated healing improvement.  A meta-analysis was not feasible due to heterogeneity in treatments parameters.  The authors concluded that available evidence suggested that laser therapy is effective in treating recurrent aphthous stomatitis; however, more randomized clinical trials are needed to compare different lasers parameters.

Fractional CO2 Laser for Male Androgenetic Alopecia

Huang and associates (2017) noted that laser therapy and growth factors have been used as alternative treatments for male androgenetic alopecia (MAA).  These researchers examined the safety and efficacy of hair growth factors alone or combined with ablative CO2 fractional laser therapy in MAA.  A total of 28 men were enrolled in this randomized half-split study based on a left-head to right-head pattern.  Fractional CO2 laser treatment was unilaterally performed; hair growth factors were bilaterally applied; 6 sessions with 2-week intervals were performed.  Global photographs and dermoscopy assessments were performed at the baseline and 4 months after 1st treatment.  Global photographs underwent blinded review by 3 independent dermatologists.  Scanning electron microscopy was used to compare changes in hair-follicle phase and hair-shaft diameter; 27 subjects completed the 4-month treatment schedule; 1 patient was lost in follow-up.  Mean hair density increased from 114 ± 27 to 143 ± 25/cm2 (p < 0.001) in the combined group and from 113 ± 24 to 134 ± 19/cm2 in the growth factor group (p < 0.001).  The mean change from baseline between 2 groups was also compared (p = 0.003).  Global photographs showed improvement in 93 % (25/27) patients in the combined group and 67 % (18/27) patients in the growth factor group.  Under scanning electron microscopy, hair follicles appeared to transition from telogen to anagen, and hair-shaft diameter increased in 5 randomly selected patients.  The authors concluded that ablative fractional CO2 laser combined with hair growth factors may serve as an alternative treatment for MAA in individuals unwilling/unable to undergo medical or surgical treatment.  This was a small study (n = 27), and its findings were confounded by the combined use of hair growth factors and CO2 fractional laser.

Salah and colleagues (2020) noted that laser treatment for hair loss has become very popular.  Laser-assisted drug delivery (LAD) is an evolving technology with potentially broad clinical applications.  These researchers examined the effect of the fractional CO2 on improving the delivery of minoxidil in patients with androgenetic alopecia and detecting the role of the fractional CO2 laser in its treatment.  They enrolled 45 Egyptians with MAA; clinical grading was assessed based on Norwood-Hamilton classification.  Subjects were divided into 3 groups: the 1st group (combined group) received the fractional CO2 laser session followed by topical application of minoxidil and also in between sessions; the 2nd group received fractional CO2 laser sessions only and 6 sessions with 2-week intervals were performed; the 3rd group applied topical minoxidil only for 3 months.  Global photographs and dermoscopic assessments were performed before treatment and 3 months after the treatment.  Several dermoscopic findings were detected, including peri-pilar sign, hair diversity, yellow spot, white dots, and arborizing red lines.  The number of double hair units significantly increased after the treatment in the combined group.  The mean number of hair after the treatment in the 3 groups significantly increased, mostly in the combined group.  The hair thickness (thin & thick) significantly increased after the treatment in the combined group and the fractional group; however, in the minoxidil group, only thin hair thickness increased.  In all the 3 groups, there was a significant improvement in hair count and thickness.  The authors concluded that ablative fractional CO2 laser alone or combined with minoxidil may serve as an additional treatment for MAA.  This was a small study (n = 15 in the fractional CO2 laser alone group) with short-term follow-up (3 months).  These preliminary findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Treatment of androgenetic alopecia in men” (Donovan et al, 2020) does not mention CO2 laser as a management/therapeutic option.

Microablative CO2 Laser for Stress Urinary Incontinence

Behnia-Willison and colleagues (2019) examined  the safety, feasibility and efficacy of trans-vaginal fractional microablative CO2 laser therapy in combination with platelet rich plasma (PRP) for the treatment of stress urinary incontinence (SUI) in women.  Patients with SUI underwent 3 sessions of transvaginal CO2 laser and PRP treatment, administered at 4- to 6-week intervals.  Outcomes were assessed using the bladder function section of the Australian Pelvic Floor Questionnaire (APFQ).  The primary outcome was changes in the subjects' symptoms of SUI; secondary outcomes were related to general bladder function.  Outcome differences from baseline (T1) to 3 months (T2) and 12 months (T3) were analyzed using Wilcoxon signed-rank tests.  Subjective verbal scales were used to evaluate the degree of pain associated with PRP injections and laser treatment.  A total of 62 women with SUI were enrolled into this study; 66 % (41/62) of subjects who reported improved SUI symptoms from T1 to T2 (p < 0.001) and at T3, 62 % (23/37) of subjects reported improved SUI symptoms (p < 0.001).  From T1 to T2, all bladder function variables improved significantly (p < 0.002).  At T3, significant improvements (p < 0.03) were maintained for all bladder function variables, except pad usage (p = 0.073).  The authors concluded that combining trans-vaginal fractional CO2 laser with PRP might be a beneficial treatment for SUI.  It may have the potential to be a minimally-invasive and low-risk alternative to surgery, with reduced recovery time.  Moreover, these researchers stated that these findings warrant further investigation into this treatment, ideally as an RCT comparing PRP and laser to a placebo and/or current treatments, including surgery.  Future research should also assess the individual contributions of the PRP and laser to the improvement of symptoms, and maintenance of treatment benefit beyond 24 months.

The authors stated that this study had several drawbacks.  First, there was no comparison of the patients receiving PRP and laser to other subjects receiving single modality treatment (PRP or laser alone).  Thus, this study could not reveal the individual contributions of PRP and the laser treatments to the improvements in SUI symptoms.  It would be important to examine the impact of topical estrogen use on vaginal mucosa with the study treatment.  Similarly, there was also no direct comparison with other current standard treatments such as the mid-urethral sling procedure, or with a control group.  A RCT is needed to confirm the findings of this study.  It would also be valuable to examine the treatment effects beyond 24 months.  Additionally, 22.6 % of women in this study were pre-menopausal.  Future studies should attempt to better represent this demographic.  Finally, there was a high attrition rate from pre-treatment (T1) to the 12 to 24 month follow-up (T3), which created a potential for bias.

CO2 Laser for the Treatment of Linear Epidermal Nevus

According to children’shealth webpage, linear epidermal nevus is a type of birthmark that is usually present at birth, but may develop later in childhood.  They are usually light or dark brown in color.  They may start as a flat area in the shape of a line or as a “skin tag”.  Over time, they grow and become thicker like a wart.  They can be located anywhere on the body.  Several topical medications (creams) can help improve the color and thickness of the lesions.  Options are mild alpha-hydroxy lotions such as over the counter Lac-Hydrin 5 %, Am Lactin 12 %, Aqua Glycolic or Eucerin Plus or bland lubricants such as Aquaphor or Vaseline.  Prescription medications that may help include Dovonex, Retin-A, or Efudex.  The only way to completely remove these lesions is to have them removed by surgery.  Laser does not permanently remove epidermal nevi.  

Molin and Sarhammar (1999) stated that inflammatory linear verrucous epidermal nevus (ILVEN) is a type of epidermal nevus with the onset usually at early childhood.  It is generally rather persistent with pruritus as a prominent symptom and is resistant to various treatments.  These investigators reported a case of disfiguring ILVEN of the vulvar area, which was treated successfully with low-fluence CO2 laser.  The patient remained improved 2 years following laser therapy.

Michel et al (2001) noted that the term LVEN refers to benign hyperplasia of the epidermis.  Three types of LVEN can be distinguished: localized, systemic and inflammatory form.  All have in common resistance to treatment and risk of recurrence.  These investigators reported the observations of 5 patients with ILVEN and 5 patients with LVEN.  Management by super-pulsed CO2 laser was performed as follows: test treatment, completed by removal of the lesion in 1 or more sessions.  Treatment was effective in all cases but 2.  Satisfactory cosmetic results were obtained; slight hyper-pigmentation, transitory desquamation and erythematous papules were observed.  There was no recurrence in 2 years follow-up.  The authors supposed that for the 2 patients with recurrence, treatment failure was due to the lower laser parameters used in these patients compared to the others, because of their younger age.

Ulkur et al (2004) stated that the treatment of an ILVEN, an uncommon type of epidermal nevus, is still controversial.  The use of laser therapy is a recently reported method.  Although various results have been reported with the use of the laser in the treatment epidermal nevis, these researchers have not seen any report on the use of the CO2 laser in ILVEN treatment.  They presented a case of ILVEN treated with CO2 laser.  All symptoms (erythema, excoriation, granulation, and pruritus) disappeared.  Instead, a pale pigmentation was observed.

D'Antuono et al (2012) noted that ILVEN is normally associated with the failure of topical and systemic treatments and with recurrences on interruption of therapy.  Many physical approaches have been used, but they generally resulted in varying rates of recurrence and unacceptable scarring.  These investigators reported a case of ILVEN treated with a single session CO2 laser treatment.  In the authors’ experience, CO2 laser was quick, easy, effective, and safe; thus, they believed that this approach should be considered as a 1st-line surgical option in the treatment of genital ILVEN, particularly in cases of mucosal involvement.

Alonso-Castro et al (2012) stated that epidermal nevi, which are benign skin growths, have been treated using a range of approaches, with varying results.  Topical treatments are ineffective and, while surgical excision is a more definitive treatment, it causes scar formation.  In recent decades, epidermal nevi have been treated with various types of laser therapy.  These investigators described their experience with the use of CO2 laser therapy to treat epidermal nevi and ILVEN.  A total of 20 patients (15 with epidermal nevi and 5 with ILVEN) underwent CO2 laser treatment at the authors’ hospital between 2002 and 2010.  Response was good (greater than 50 % reduction in lesion size) in 50 % of cases and excellent (greater than 75 % reduction) in 30 %.  A greater resistance to treatment was observed in patients with ILVEN (only 40 % had a good response).  Long-term follow-up (at least 18 months) showed a recurrence rate of 30 %.  The side effects were hypo-pigmentation (25 % of patients) and scarring (20 %).  The authors considered CO2 laser therapy to be the treatment of choice for epidermal nevi as it was well-tolerated and has proven to be safe and effective in the long-term.  Moreover, these researchers stated that while the response in patients with ILVEN was limited, CO2 laser therapy might be a good option for selected cases or for palliative treatment since no other treatments have yet proven effective in this setting.

Borzecki et al (2016) noted that linear epidermal nevus is a congenital malformation characterized by linear, often 1-sided arrangement.  The lesions are localized along the Blaschko's lines, are present at birth, or appear in early childhood.  They can be single or multiple, and have various colors-from skin color to dark brown.  These lesions persist through the whole life making a significant cosmetic defect.  These investigators presented 3 cases of epidermal nevus treated with CO2 laser.  In a female patient, verrucous, dark brown skin eruptions were observed at the back of earlobe and down the neck.  In the cases of the male patients, the lesions were located in the area of the neck and left blade.  The removal of nevi was performed in stages, by cutting and evaporation using a CO2 laser.  A very good therapeutic effect was obtained.  The authors concluded that CO2 laser treatment is the method of choice for the removal of extensive epidermal nevi.  It is characterized by its safety and high efficacy.

Furthermore, an UpToDate review on “Epidermal nevus and epidermal nevus syndrome” (Wright, 2021) states that “Epidermal nevi are benign, hamartomatous growths of the skin that are present at birth or develop in early childhood … Laser therapy is used increasingly for the treatment of epidermal nevi; improvements in technology and better selection of modality are gradually overcoming problems such as hypertrophic scarring, pigmentary changes, and partial recurrence.  Continuous wave and pulsed carbon dioxide (CO2) laser vaporization has been used with good results in patients with soft, flat epidermal nevi.  Erbium:yttrium aluminum garnet (Er:YAG) laser ablation may provide better cosmetic results than CO2 laser with minimal or no scarring.  In a series of 20 patients with verrucous epidermal nevi treated with Er:YAG laser, healing occurred within 10 days without scarring.  However, recurrence was reported in 5 of 20 patients in 3 to 12 months”.

Fractional CO2 Laser Combined with Narrow-Band Ultraviolet B Phototherapy for the Treatment of Vitiligo

Esme and associates (2020) Narrow-band ultra-violet B (NB-UVB) phototherapy constitutes the gold standard for the treatment of vitiligo.  Whether CO2 laser might increase the efficacy of NB-UVB is still a topic of debate.  In a prospective, randomized study, these researchers tested the hypothesis that the combined use of fractional CO2 laser and NB-UVB may enhance re-pigmentation.  Fractional CO2 laser was administered with an interval of 2 weeks for 7 sessions, only to 1 of the 2 symmetrical vitiligo patches located on 2 different half-body sides.  Patients received whole-body NB-UVB phototherapy thrice-weekly for at least 4 months.  Re-pigmentation was recorded with a quartile grading scale, with the aid of a computer program using the photographs taken by the digital dermatoscopy.  A total of 51 symmetrical vitiligo patches of 30 patients were included.  No statistically significant difference was observed between the mean re-pigmentation scores for the laser and non-laser sides (p = 0.11).  The authors concluded that findings of this study suggested that combining fractional CO2 laser with NB-UVB phototherapy with the regimen used in this study did not increase the re-pigmentation scores for vitiligo.

In a systematic review and meta-analysis, Kim and colleagues (2021) examined the safety and efficacy of fractional CO2 laser combined with NB-UVB compared with NB-UVB alone for the treatment of stable non-segmental vitiligo.  These investigators searched for available evidence from different databases, including Cochrane, Embase, and PubMed up to January 2020.  A total of 4 RCTs for comparison between fractional CO2 laser plus NB-UVB and NB-UVB alone in patients with stable non-segmental vitiligo were included.  These researchers carried out meta-analyses for re-pigmentation improvement and patient satisfaction as well as subgroup analyses based on acral or non-acral vitiligo, according to the PRISMA guidelines.  The combination treatment showed more superior results than NB-UVB monotherapy (greater than or equal to  75 % re-pigmentation, RR 4.60, 95 % CI: 1.19 to 17.74; greater than or equal to 50 % re-pigmentation, RR 2.24, 95 % CI: 0.45 to 11.17; less than 25 % re-pigmentation, RR 0.81, 95 % CI: 0.60 to 1.08).  Furthermore, fractional CO2 laser plus NB-UVB significantly improved acral and non-acral vitiligo compared with NB-UVB monotherapy (standard mean difference (SMD) 1.24, 95 % CI: 0.66 to 1.82; SMD 1.14, 95 % CI: 0.67 to 1.60, respectively), while it increased markedly patient satisfaction compared with NB-UVB monotherapy (SMD 1.12, 95 % CI: 0.66 to 1.58).  The authors concluded that the findings of this meta-analysis suggested that fractional CO2 laser combined with NB-UVB might be more effective for treating non-segmental vitiligo than NB-UVB monotherapy.

Furthermore, an UpToDate review on “Vitiligo: Management and prognosis” (Grimes, 2021) does not mention CO2 laser as a management / therapeutic option.

The above policy is based on the following references: