Prior Authorization Review Panel MCO Policy Submission A ......sheeting is used to reduce the volume and increase the elasticity of hypertrophic and keloid scars, as a dressing for

Prior Authorization Review Panel MCO Policy Submission

A separate copy of this form must accompany each policy submitted for review.Policies submitted without this form will not be considered for review.

Plan: Aetna Better Health Submission Date:07/01/2019

Policy Number: 0389 Effective Date: Revision Date: 06/20/2019

Policy Name: Hypertrophic Scars and Keloids

Type of Submission – Check all that apply: New Policy Revised Policy* Annual Review – No Revisions

*All revisions to the policy must be highlighted using track changes throughout the document. Please provide any clarifying information for the policy below:

CPB 0389 Hypertrophic Scars and Keloids

This CPB has been revised to state that the following are considered experimental and investigational: (i) Losartan ointment and topical oxandrolone for the treatment of hypertrophic scars and keloids; (ii) fractional ablative laser for the treatment of burn scar; and (iii) intralesional fiber laser device for the treatment of keloids.

Update History since the last PARP Submission:

03/12/2019-This CPB has been updated with additional coding.

Name of Authorized Individual (Please type or print):

Dr. Bernard Lewin, M.D.

Signature of Authorized Individual:

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(https://www.aetna.com/)

Hypertrophic Scars and Keloids

Clinical Policy Bulletins Medical Clinical Policy Bulletins

Policy History

Last Revi

ew

06/20/2019

Effective: 10/04/200

Next Review:

04/10/2020

Review Hi

story

Definitions

Additional Information

Number: 0389

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

Aetna considers intralesional 5-fluorouracil, cryotherapy or corticosteroids medically

necessary for treatment of keloids where medical necessity criteria for keloid

removal are met. See CPB 0031 - Cosmetic Surgery (../1_99/0031.html), for

medically necessary indications for keloid removal.

Aetna considers the following interventions experimental and investigational for the

treatment of hypertrophic scars or keloids because of insufficient evidence in the

peer-reviewed literature:

▪ Adipose-derived stem cell

▪ Anti-vascular endothelial growth factor therapy (e.g., bevacizumab)

▪ Autologous fat grafting

▪ Basic fibroblast growth factor

▪ Calcium antagonists

▪ Dermal substitutes

▪ Etanercept (see CPB 0315 - Enbrel (Etanercept) (0315.html))

▪ Extracorporeal shock wave therapy

◾ Fractional ablative laser (for the treatment of burn scar)

▪ Growth hormone-releasing peptide 6

http://www.aetna.com/cpb/medical/data/300_399/0389.html 06/28/2019

http://www.aetna.com/cpb/medical/data/300_399/0389.html

https://www.aetna.com/

Page 2 of 50

▪

Hyaluronidase

▪ Hyperbaric oxygen therapy

▪ Imiquimod cream

▪ Intense pulsed light

▪ Interferon alpha (see CPB 0404 - Interferons (../400_499/0404.html))

▪ Intralesional bleomycin

▪ Intralesional botulinum toxin type A injection

▪ Intralesional fiber laser device (for the treatment of keloids)

▪ Intralesional mitomycin

▪ Laser-assisted administration of corticosteroid

▪ Losartan ointment

▪ Mesenchymal stem cells

▪ Micro-needling (with Dermapen disposable tips or other devices/tools)

▪ Non-ablative fractional laser

▪ Radiofrequency treatment

▪ Silicone products (e.g., gel, rigid shells, sheeting)

▪ Topical calcipotriol

▪ Topical oxandrolone

▪ Topical retinoids

▪ Transforming growth factor beta1

See also CPB 0062 - Burn Garments (../1_99/0062.html),

CPB 0244 - Wound Care (../200_299/0244.html),

CPB 0551 - Radiation Treatment for Selected Nononcologic Indications

(../500_599/0551.html),

and CPB 0559 - Pulsed Dye Laser Treatment (../500_599/0559.html).

Background

Keloids and hypertrophic scars develop as a result of a proliferation of dermal

tissue following skin injury, and are common (keloids develop in 5 % to 15 % of

wounds).



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Topical silicone gel sfheeting is a soft, slightly adherent, semi-occlusive covering

which is fabricated from medical grade silicone polymers. Topical silicone gel

sheeting is used to reduce the volume and increase the elasticity of hypertrophic

and keloid scars, as a dressing for both donor and recipient sites in skin grafting,

fand as a treatment of burn wounds.

Examples of brands of silicone gel sheeting available over-the-counter include: Sil-

K, Cica-Care, ReJuveness, DuraSil and Silastic Gel Sheeting. Epi-Derm brand of

silicone gel sheeting is currently available only by prescription, although the

manufacturer of Epi-Derm is pursuing Food and Drug Administration

(FDA) clearance for over-the-counter marketing.

Silicone has also been applied as a gel or as rigid custom-molded shell to scars,

burns, and skin grafts. Although several case series have reported improvements

in the appearance (scar size, erythema, elasticity) and symptoms (pruritus, burning

pain) from the application of silicone sheets, gels, or shells to hypertrophic scars

and keloids, these promising results have not been confirmed by subsequent

prospective randomized controlled trials (RCTs). Prospective RCTs of silicone

products in treatment of hypertrophic scars and keloids are limited, and the

outcomes of these studies have not consistently demonstrated a clinically

significant benefit of silicone products in treating hypertrophic scars or keloids over

standard wound dressings.

In an open-label pilot study, Lacarrubba et al (2008) assessed the effectiveness

and tolerability of a silicone gel in the treatment of hypertrophic scars. A topical self-

drying silicone gel containing polysiloxane and silicone dioxide was applied twice-

daily in 8 hypertrophic scars. After 6 months, all lesions showed evident clinical

and/or ultrasound improvement, with a mean scar thickness reduction of 37

% (range of 20 % to 54 %). The authors stated that although controlled trials in

larger series of patients are necessary, these findings suggested that the self-

drying silicone gel may represent a safe and effective treatment for hypertrophic

scars.

In a prospective, single-blind, RCT, Wittenberg et al (1999) evaluated the

effectiveness of the 585-nm flashlamp-pumped pulsed-dye laser and silicone gel

sheeting in the treatment of hypertrophic scars in lighter-skinned and darker-

skinned patients: 19 completed the laser treatments and 18 completed the silicone

gel sheeting treatments. Clinical measurements included hypertrophic scar blood



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flow, elasticity, and volume. Patients' subjective complaints of pruritus, pain, and

burning were also monitored. Histological assessment of fibrosis, number of

telangiectasias, and number of mast cells was performed. Statistically significant

improvements in clinical measurements and patients' subjective complaints

determined treatment success. These investigators concluded that clinical results

demonstrate that the improvements in scar sections treated with silicone gel

sheeting and pulsed-dye laser were no different than those in control sections.

In a discussion of treatment of keloids, Quintal (2002) concluded that “[m]ore in-

depth, controlled research is needed to prove or disclaim the therapeutic effect of

silicone.” A recently published systematic review of the literature on treatment of

keloid scars concluded that “[t]he effectiveness of silicone gel sheeting and other

occlusive dressings in treating keloidal scars cannot be confirmed by existing

studies” (Shaffer et al, 2002).

The FDA (2004) classified silicone sheeting intended for use in the management of

closed hyper-proliferative (hypertrophic and keloid) scars into class I (general

controls). As a class I device, the device will be exempt from premarket notification

requirements.

In a prospective, randomized, placebo-controlled, clinical trial that examined the

use of silicone gel in preventing hypertrophic scar development in median

sternotomy wound, Chan et al (2005) concluded that the effect of silicone gel in the

prevention of hypertrophic scar development in sternotomy wounds is promising. In

a recent review on keloid pathogenesis and treatment, Al-Attar and colleagues

(2006) noted that established treatment strategies for keloids include surgery,

steroid, and radiation (silicone was not listed as an established treatment for

keloids).

A structured assessment of the evidence of silicone gel sheeting for preventing and

treating hypertrophic scars and keloids prepared for the Cochrane Collaboration

reached the following conclusions (O'Brien and Pandit, 2006): “Trials evaluating

silicon gel sheeting as a treatment for hypertrophic and keloid scarring are of poor

quality and highly susceptible to bias. There is weak evidence of a benefit of silicon

gel sheeting as a prevention for abnormal scarring in high risk individuals but the

poor quality of research means a great deal of uncertainty prevails.”



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Stavrou et al (2010) stated that hypertrophic and keloid scars still are among the

banes of plastic surgery. In the treatment arsenal at the disposal of the plastic

surgeon, topical silicone therapy usually is considered the first line of treatment or

as an adjuvant to other treatment methods. Yet, knowledge concerning its

mechanisms of action, clinical efficacy, and possible adverse effects is rather

obscure and sometimes conflicting. The author summarized the existing literature

regarding the silicone elastomer's mechanism of action on scars, the clinical trials

regarding its efficacy, a description of some controversial points and contradicting

evidence, and possible adverse effects of this treatment method. Topical silicone

therapy probably will continue to be the preferred first-line treatment for

hypertrophic scars due to its availability, price, ease of application, lack of serious

adverse effects, and relative efficacy. Hopefully, future RCTs will help to clarify its

exact clinical efficacy and appropriate treatment protocols to optimize treatment

results.

In a single-center placebo-controlled double-blind trial, Stoffels et al

(2010) examined the impact of silicone spray on scar formation. These

investigators reported that after 3 months of treatment the Patient Scar Assessment

Scale demonstrated that patient satisfaction with the silicone application was

significantly higher compared to placebo. However, when treatment was stopped

after 3 months, the topical silicone spray did not exhibit any lasting long-term

impact on the objective results of scar formation.

In a review on "Prevention and management of keloid scars", Lutgendorf et al

(2011) noted that "[a]lthough silicone gel sheeting is a well-accepted treatment

modality, the studies to date provide level IV evidence, with a lack of controls and

increased susceptibility to bias. A recent Cochrane systematic review on the use of

silicone gel sheeting for preventing and treating hypertrophic and keloid scars found

that any effects were obscured by the poor quality of research".

Several clinical trials have demonstrated the effectiveness of intralesional

5-fluorouracil in the treatment of keloid scarring (Asilian et al, 2006; Nanda and

Reddy, 2004; and Manuskiatti and Fitzpatrick, 2002). Asilian and colleagues

(2006) examined the effectiveness of a combination of intralesional steroid,

5-fluorouracil (5-FU), and pulsed-dye laser in the treatment of hypertrophic scars

and keloids. A total fo 69 patients were randomly assigned to treatment with

intralesional triamcinolone acetonide (TA), intralesional TA plus intralesional 5-FU,

and TA, 5-FU and pulse-dye laser treatment. The investigators reported that, after



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12 weeks, good to excellent improvements were reported by a blinded observer in

15 % of subjects treated with TA alone, 40 % of subjects treated with TA plus 5-FU,

and 70 % of subjects treated with all 3 modalities.

Tosa et al (2009) stated that because intralesional injection of TA, a widely used for

the treatment of keloid, is painful, many patients discontinue treatment. These

researchers evaluated the effects of pre-treatment with topical 60 % lidocaine tape

on the pain and tolerability of intralesional TA treatment in patients with keloid. The

subjects were 42 patients with keloid who had been treated with intralesional

injection of TA but had discontinued treatment owing to intolerable pain. All

patients were pre-treated with 60 % lidocaine tape placed on the keloids for more

than 120 mins before intralesional injection of TA. Patients assessed pain with a 100-

mm visual analog scale (VAS) with 0 mm for "no pain" and 100 mm for "worst

possible pain". Pain was assessed with the VAS immediately after TA injection.

Finally, the patients assessed the tolerability of this treatment. The mean VAS

score during intralesional TA injection therapy without pre-treatment with lidocaine

tape was 82.6 +/- 14.4 mm. In contrast, the mean VAS score during intralesional

TA injection therapy in the same patients after pre-treatment with lidocaine tape

was 18.9 +/- 11.3 mm, which was significantly lower (p < 0.05), and 30 (71.4 %) of

the patients tolerated this therapy well. Pre-treatment with 60 % lidocaine tape

significantly reduces the pain associated with intralesional injection of TA. This

approach increases patient comfort and should enable patients to continue the

treatment.

Pai and Cummings (2011) examined if surgical excision with or without adjuvant

treatment beneficial in reducing the size of the scar in patients with hypertrophic

and keloid scarring of the sternotomy wound. More than 15 papers were found

using the reported search, of which 9 represented the best evidence to address this

clinical issue. The authors, journal, date and country of publication, patient group

studied, study type, relevant outcomes and results of these papers were tabulated.

One of the studies showed no difference between surgery and adjunctive TA or

colchicine. One study showed that incomplete excision resulted in higher

recurrence rates. Post-operative radiation was found to be useful in 2 of the

studies, although 1 study showed that it was not useful. One RCT showed

improvement after laser compared to no treatment; 2 other trials showed no

difference between laser, silicone gel, intralesional steroid or 5-FU. One trial

showed that peri-operative systemic steroid application gave rise to no

improvement but in fact worsened scar formation. The authors concluded that



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small keloids can be treated radically by surgery with adjuvant therapy (radiation or

corticosteroid injections) or by non-surgical therapy (corticosteroid injections, laser

and anti-tumour/immunosuppressive agents, such as 5-fFU). Large and multiple

keloids are difficult to treat radically and are currently only treatable by multi-modal

therapies that aim to relieve symptoms.

An UpToDate review on "Keloids" (Goldstein and Goldstein, 2012) states that "[i]

ntralesional corticosteroids are first-line therapy for most keloids. A systematic

review found that up to 70 percent of patients respond to intralesional corticosteroid

injection with flattening of keloids, although the recurrence rate is high in some

studies (up to 50 percent at five years)".

Meshkinpour et al (2005) examined the safety and effectiveness of the ThermaCool

TC radiofrequency system for treatment of hypertrophic and keloid scars and

assessed treatment associated collagen changes. Six subjects with hypertrophic

and 4 with keloid scars were treated with the ThermaCool device: 1/3 of the scar

received no treatment (control), 1/3 received one treatment and 1/3 received 2

treatments (4-week interval). Scars were graded before and then 12 and 24 weeks

after treatment on symptoms, pigmentation, vascularity, pliability, and height.

Biopsies were taken from 4 subjects with hypertrophic scars and evaluated with

hematoxylin and eosin (H & E) staining, multi-photon microscopy, and pro-collagen

I and III immunohistochemistry. No adverse treatment effects occurred. Clinical

and H & E evaluation revealed no significant differences between control and

treatment sites. Differences in collagen morphology were detected in some

subjects. Increased collagen production (type III > type I) was observed, appeared

to peak between 6 and 10 weeks post-treatment and had not returned to baseline

even after 12 weeks. The authors concluded that use of the thermage

radiofrequency device on hypertrophic scars resulted in collagen fibril morphology

and production changes. ThermaCool alone did not achieve clinical hypertrophic

scar or keloid improvement. They noted that the collagen effects of this device

should be studied further to optimize its therapeutic potential for all indications.

Davison et al (2006) ascertained the effectiveness of interferon alpha-2b in keloid

management. These investigators prospectively assessed the effects of interferon

alpha-2b as post-excisional adjuvant therapy for keloids. A total of 39 keloids in 34

patients were photographed, measured, and surgically excised. The wound bed

was injected twice with either interferon alpha-2b (treatment group; n = 13 keloids)

or TA (control group; n = 26 keloids) at surgery and 1 week later. The patients



Page 8 of 50

were followed- up in the plastic surgery clinic. The trial protocol was terminated at

mid-trial surveillance. Among the 13 keloids that were treated with post-operative

intralesional interferon alpha-2b, 7 recurred (54 % recurrence rate). In contrast, in

the 26 keloids that received TA (control group), only 4 recurred (15 % recurrence

rate). Recurrence in either group did not correlate with location of the keloid or

race. The authors concluded that interferon does not appear to be effective in the

clinical management of keloids. This finding is consistent with an earlier controlled

trial which also found a lack of effectiveness of intralesional interferon alpha in the

treatment of keloids (al-Khawajah, 1996).

Al-Attar et al (2006) reviewed the major concepts of keloid pathogenesis and the

treatment options stemming from them. They noted that mechanisms for keloid

formation include alterations in growth factors, collagen turnover, tension alignment,

and genetic and immunologic contributions. Treatment strategies for keloids

include established (e.g., surgery, steroid, radiation) and experimental (e.g.,

interferon, retinoid) regimens. The authors concluded that combination therapy,

using surgical excision followed by intra-dermal steroid or other adjuvant therapy,

currently appears to be the most effective and safe current regimen for keloid

management.

Sharma and colleagues (2007) compared the effectiveness of liquid nitrogen

cryosurgery alone with liquid nitrogen cryosurgery plus intralesional TA combination

in the treatment of keloids (n = 21; 60 clinically diagnosed lesions of keloids). The

statistical analysis showed synergistic action of cryosurgery and corticosteroids

may offer promise in the treatment. Karrer (2007) noted that keloids are a

therapeutic challenge for dermatologists. Although multiple therapeutic options are

available, a reliably effective approach with few side effects remains elusive. High

quality research in evaluating the effectiveness of keloid therapy is also lacking.

This is in agreement with the findings of Durani and Bayat (2008) who reported that

the level of evidence (LOE) of cryosurgery in the treatment of keloids is 4 (LOE-1

denotes highest quality while LOE-5 denotes lowest quality).

Berman et al (2008) evaluated the tolerability and efficacy of etanercept as

compared to TA for the treatment of keloids. A total of 20 subjects were randomly

assigned to receive monthly intralesional injections of either 25 mg of etanercept or

20 mg of TA for 2 months. Keloids were evaluated at baseline, week 4, and week 8

by subjects and investigators in a blinded fashion using physical, clinical, and

cosmetic parameters. Photographs were taken and adverse events were noted



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during each evaluation. Etanercept improved 5/12 parameters including significant

pruritus reduction, while TA improved 11/12 parameters at week 8, although no

statistical difference was observed as compared to baseline. There was no

significant difference between the 2 treatment groups. The authors concluded

that etanercept was safe, well-tolerated, improved several keloid parameters, and

reduced pruritus to a greater degree than TA therapy. However, they noted that

further studies are needed before it can be recommended for the treatment of

keloids.

Berman (2010) stated that the potential of various biological agents to reduce or

prevent excessive scar formation has now been evaluated in numerous in-vitro

studies, experimental animal models and preliminary clinical trials, in some cases

with particularly promising results. Perhaps prominent among this group of

biological agents, and, to some degree, possibly representing marketed

compounds already being used "off label" to manage excessive scarring, are the

tumor necrosis factor alpha antagonist, etanercept, and immune-response

modifiers such as interferon-alpha2b and imiquimod. The author noted that

additional assessment of these novel agents is now justified with a view to reducing

or preventing hypertrophic scars, keloid scars and the recurrence of post-excision

keloid lesions.

In a meta-analysis, Anzarut et al (2009) evaluated the effectiveness of pressure

garment therapy (PGT) for the prevention of abnormal scarring after burn injury.

Randomized control trials were identified from CINHAL, EMBASE, MEDLINE,

CENTRAL, the "grey literature" and hand searching of the Proceedings of the

American Burn Association. Primary authors and pressure garment manufacturers

were contacted to identify eligible trials. Bibliographies from included studies and

reviews were searched. Study results were pooled to yield weighted mean

differences or standardized mean difference and reported using 95 % confidence

interval (CI). The review incorporated 6 unique trials involving 316 patients.

Original data from 1 unpublished trial were included. Overall, studies were

considered to be of high methodological quality. The meta-analysis was unable to

demonstrate a difference between global assessments of PGT-treated scars and

control scars [weighted mean differences (WMD): -0.46; 95 % CI: -1.07 to 0.16].

The meta-analysis for scar height showed a small, but statistically significant,

decrease in height for the PGT-treated group standardized mean differences

(SMD): -0.31; 95 % CI: -0.63 to 0.00. Results of meta-analyses of secondary

outcome measures of scar vascularity, pliability and colour failed to demonstrate a



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difference between groups. The authors concluded that PGT does not appear to

alter global scar scores. It does appear to improve scar height, although this

difference is small and of questionable clinical importance. The beneficial effects of

PGT remain unproven, while the potential morbidity and cost are not insignificant.

Given current evidence, additional research is needed to examine the

effectiveness, risks and costs of PGT.

In a prospective, randomized, clinical trial, Xiao et al (2009) examined the

effectiveness of intralesional botulinum toxin type A (BTX-A) injections in the

treatment of hypertrophic scars. A total of 19 patients were enrolled in this study.

At 1-month intervals, BTX-A (2.5 U per cubic centimeter of lesion) was injected in

these patients for a total of 3 months. All the patients were followed-up for at least

half a year. Therapeutic satisfaction was recorded, and the lesions were assessed

for erythema, itching sensation, and pliability. At the half-year follow-up visits, all

the patients showed acceptable improvement, and the rate of therapeutic

satisfaction was very high. The erythema score, itching sensation score, and

pliability score after the BTX-A injection all were significantly lower than before the

BTX-A injection. The differences all were statistically significant (p < 0.01). The

authors concluded that for the treatment of hypertrophic scars, doctors and patients

both found BTX-A acceptable because of its better therapeutic results. Its effect of

eliminating or decreasing hypertrophic scars was promising. The findings of this

preliminary report need to be validated by further investigation.

In a randomized, double-blind, placebo-controlled trial using the reduction

mammoplasty wound-healing model, van der Veer et al (2009) assessed

the effectiveness of topical application of calcipotriol (a synthetic derivative of

calcitriol or vitamin D) to healing wounds in preventing or reducing hypertrophic

scar formation and investigated the biochemical properties of the epidermis

associated with hypertrophic scar formation. A total of 30 women who underwent

bilateral reduction mammoplasty were included in this study. For 3 months, scar

segments were treated with either topical calcipotriol or placebo. Three weeks, 3

months, and 12 months post-operatively, the scars were evaluated and punch

biopsy samples were collected for immuno-histochemical analysis. No significant

difference in the prevalence of hypertrophic scars was observed between the

placebo-treated and calcipotriol-treated scars. Only scars with activated

keratinocytes 3 weeks post-operatively became hypertrophic (p = 0.001). The

authors concluded that topical application of calcipotriol during the first 3 months of

wound healing does not affect the incidence of hypertrophic scar formation.



Page 11 of 50

Hayashida and Akita (2012) stated that pediatric burn wounds present unique

challenges. Second-degree burns may increase in size and depth, raising

concerns about healing and long-term scarring. Results of a clinical study in adults

with second-degree burn wounds suggested that application of basic fibroblast

growth factor may reduce time to second-intention healing and result in a more

cosmetically acceptable scar. These investigators evaluated the effect of this

treatment on pediatric patients with deep second- degree burn wounds, 20 pediatric

patients ranging in age from 8 months to 3 years (average of 1 year, 3 months [+/-

6 months]) with a total of 30 burn wounds from various causes were allocated either

the growth factor (treatment, n = 15) or an impregnated gauze treatment (control, n

= 15). Wounds, which still exudative (not healed) after 21 days, were covered with

a split-thickness skin graft. All wounds were clinically assessed until healed and

after 1 year. A moisture meter was used to assess scars of wounds healing by

secondary intention. A color meter was used to evaluate grafted wounds. Five

wounds in each group required grafting. Skin/scar color match was significantly

closer to 100 % in the treatment than in the control group (p <0.01). Wounds not

requiring grafting were no longer exudative after 13.8 (+/- 2.4) and 17.5 (+/- 3.1)

days in the treatment (n = 10) and control group (n = 10), respectively (p <0.01).

After 1 year, scar pigmentation, pliability, height, and vascularity were also

significantly different (p <0.01) between the groups. Hypertrophic scars developed

in 0 of 10 wounds in the treatment and in 3 of 10 wounds in the control group, and

effective contact coefficient, trans-epidermal water loss, water content, and scar

thickness were significantly greater in control group (p <0.01). The authors

concluded that both the short- and long-term results of this treatment in pediatric

burn patients are encouraging and warrant further research.

Verhaeghe et al (2013) noted that non-ablative fractional laser (NAFL) therapy is a

non-invasive procedure that has been suggested as a treatment option for

hypertrophic scars. These researchers evaluated the safety and effectiveness of

1,540-nm NAFL therapy in the treatment of hypertrophic scars. An intra-individual

RCT with split lesion design and single-blinded outcome evaluations was

performed. Patients received 4 NAFL treatments at monthly intervals. Primary end-

point was a blinded on-site visual and palpable Physician Global Assessment

(PhGA). Adverse event registration and pain evaluation were used to evaluate

safety. Patient global assessment (PGA) was a secondary endpoint to additionally

evaluate effectiveness. The PhGA did not find a statistically significant difference

between the treated and untreated control side of 18 patients, although there was

significant difference on the PGA at 1 month (p =0 .006) and 3 months (p = 0.02)



Page 12 of 50

after last treatment (Wilcoxon signed rank test). Patients experienced moderate

pain during treatment and mild adverse events. The authors concluded that in this

trial, blinded PhGA could not confirm the clinical effectiveness of 1,540-nm non-

ablative fractional laser in the treatment of hypertrophic scars, but the treatment is

safe, and patients judged that the treated part had a better global appearance.

Waibel et al (2013) stated that hypertrophic scars and contractures are common

following various types of trauma and procedures despite skilled surgical and

wound care. Following ample time for healing and scar maturation, many millions

of patients are burdened with persistent symptoms and functional impairments.

Cutaneous scars can be complex and thus the approach to therapy is often multi-

modal. Intralesional corticosteroids have long been a staple in the treatment of

hypertrophic and restrictive scars. Recent advances in laser technology and

applications now provide additional options for improvements in function,

symptoms, and cosmesis. Fractional ablative lasers create zones of ablation at

variable depths of the skin with the subsequent induction of a wound healing and

collagen remodeling response. Recent reports suggested these ablative zones

may also be used in the immediate post-operative period to enhance delivery of

drugs and other substances. These researchers presented a case series

evaluating the effectiveness of a novel combination therapy that incorporates the

use of an ablative fractional laser with topically applied triamcinolone acetonide

suspension in the immediate post-operative period. This was a prospective case

series including 15 consecutive subjects with hypertrophic scars resulting from

burns, surgery or traumatic injuries. Subjects were treated according to typical

institutional protocol with 3 to 5 treatment sessions at 2- to 3-month intervals

consisting of fractional ablative laser treatment and immediate post-operative

topical application of triamcinolone acetonide suspension at a concentration of 10

or 20 mg/ml. Three blinded observers evaluated photographs taken at baseline

and 6 months after the final treatment session. Scores were assigned using a

modified Manchester quartile score to evaluate enhancements in dyschromia,

hypertrophy, texture, and overall improvement. Combination same session laser

therapy and immediate post-operative corticosteroid delivery resulted in average

overall improvement of 2.73/3.0. Dyschromia showed the least amount of

improvement while texture showed the most improvement. The authors concluded

that combination same-session therapy with ablative fractional laser-assisted

delivery of triamcinolone acetonide potentially offers an efficient, safe and effective

combination therapy for challenging hypertrophic and restrictive cutaneous scars.



Page 13 of 50

The main drawbacks of this study were its small sample size and the lack of a

control arm. These preliminary findings need to be validated by well-designed

studies.

Jin and colleagues (2013) performed a meta-analysis to evaluate the effectiveness

of various laser therapies for prevention and treatment of pathologic excessive

scars. The pooled response rate, pooled standardized mean difference of

Vancouver Scar Scale scores, scar height, erythema, and pliability were reported.

A total of 28 well-designed clinical trials with 919 patients were included in the meta-

analysis. The overall response rate for laser therapy was 71 % for scar prevention,

68 % for hypertrophic scar treatment, and 72 % for keloid treatment.

The 585/595-nm pulsed-dye laser and 532-nm laser subgroups yielded the best

responses among all laser systems. The pooled estimates of hypertrophic scar

studies also showed that laser therapy reduced total Vancouver Scar Scale scores,

scar height, and scar erythema of hypertrophic scars. Regression analyses of

pulsed-dye laser therapy suggested that the optimal treatment interval is 5 to 6

weeks. In addition, the therapeutic effect of pulsed-dye laser therapy is better on

patients with lower Fitzpatrick skin type scores. The authors concluded that this

study presented the first meta-analysis to confirm the safety and effectiveness of

laser therapy in hypertrophic scar management. The level of evidence for laser

therapy as a keloid treatment is low. Moreover, they stated that further research is

needed to determine the mechanism of action for different laser systems and to

examine the effectiveness in quantifiable parameters, such as scar erythema, scar

texture, degrees of symptom relief, recurrence rates, and adverse effects.

In a Cochrane review, O'Brien and Jones (2013) examined the effectiveness of

silicone gel sheeting for: (i) prevention of hypertrophic or keloid scarring in

people with newly healed wounds (e.g., post-surgery); (ii) treatment of

established scarring in people with existing keloid or hypertrophic scars. In

May 2013 these investigators searched the Cochrane Wounds Group Specialised

Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid

MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid

EMBASE; and EBSCO CINAHL for this second update. Any randomized or quasi-

RCTs, or controlled clinical trials, comparing silicone gel sheeting for prevention or

treatment of hypertrophic or keloid scars with any other non-surgical treatment, no

treatment or placebo were selected for analysis. These researchers assessed all

relevant trials for methodological quality. Three review authors extracted data

independently using a standardized form and cross-checked the results. They



Page 14 of 50

assessed all trials meeting the selection criteria for methodological quality. The

authors included 20 trials involving 873 people, ranging in age from 1.5 to 81 years.

The trials compared adhesive silicone gel sheeting with no treatment; non silicone

dressing; other silicone products; laser therapy; triamcinolone acetonide injection;

topical onion extract and pressure therapy. In the prevention studies, when

compared with a no treatment option, while silicone gel sheeting reduced the

incidence of hypertrophic scarring in people prone to scarring (risk ratio (RR) 0.46,

95 % CI: 0.21 to 0.98) these studies were highly susceptible to bias. In treatment

studies, silicone gel sheeting produced a statistically significant reduction in scar

thickness (MD -2.00, 95 % CI: -2.14 to -1.85) and color amelioration (RR 3.49, 95

% CI: 1.97 to 6.15) but again these studies were highly susceptible to bias. The

authors concluded that there is weak evidence of a benefit of silicone gel sheeting

as a prevention for abnormal scarring in high-risk individuals but the poor quality of

research means a great deal of uncertainty prevails. Moreover, they stated that

trials evaluating silicone gel sheeting as a treatment for hypertrophic and keloid

scarring showed improvements in scar thickness and scar color, but were of poor

quality and highly susceptible to bias.

Malhotra et al (2007) evaluated the safety and effectiveness of imiquimod 5 %

cream in preventing the recurrence of pre-sternal keloids after excision (3 keloids in

2 patients). After excision with radiofrequency (RF), imiquimod 5 % cream was

applied once-daily at bedtime for 8 weeks, and the defect was left to heal by

secondary intention. In all the treated keloids, the defect healed in 6 to 8 weeks,

and no recurrence was seen while on imiquimod application; however, all keloids

completely recurred within 4 weeks of stopping imiquimod. Side effects were mild

and acceptable in the form of burning and pain. The authors concluded that

imiquimod did exert an anti-fibrotic action but it was short-lived.

In a prospective, double-blind, placebo-controlled pilot study, Berman et al (2007)

determined the tolerability and compare the effectiveness of imiquimod 5 % and

vehicle cream in lowering keloid recurrence after shaving. A total of 20

randomized, shaved keloids were administered imiquimod 5 % or vehicle cream

nightly for 2 weeks, and then given 3 times a week under occlusion for 1 month.

Pain, tenderness, pruritus and keloid recurrence were evaluated at baseline, week

2, week 6 and 6 months. Tenderness and pain were significantly (p = 0. 02 and p =

0. 02, respectively) higher at week 2 in the imiquimod group than for those treated

with vehicle cream. Pruritus did not attain statistical difference between the

groups. At 6 months, keloid recurrence rates were 37.5 % (3/8) in the imiquimod



Page 15 of 50

group and 75 % (3/4) in the vehicle group (p = 0.54). The authors concluded that

imiquimod was well-tolerated. However, there was not enough statistical power to

detect a significant difference in 6-month keloid recurrence rates between the

imiquimod-treated group and the vehicle-treated group.

Cacao et al (2009) evaluated the effectiveness of topical imiquimod 5 % cream

applied after surgical excision and primary closure of trunk keloids in the prevention

of recurrence. A total of 9 patients with a keloid lesion on the trunk were treated

with surgical excision and primary closure. Daily application of imiquimod 5 %

cream for 8 weeks was initiated the night of surgery. The patients were evaluated

2, 4, 8, 12, and 20 weeks after. Keloid recurrence occurred in 8 patients, 7 of them

12 weeks after surgery. These researchers lost track of 1 patient. The authors

concluded that the results of this study suggested that imiquimod 5 % cream is not

effective in preventing recurrence of trunk keloids after surgical excision. They

stated that although this was a small case series, results strongly discouraged other

studies using imiquimod 5 % cream in the prevention of surgically excised trunk

keloids.

Viera et al (2012) stated that there is very limited evidence on the best wound

management for minimizing scarring. Multiple available therapeutic modalities

have been used for the treatment of keloids; however, high-recurrence rates

continue to be reported. Currently, there are biological and anti-neoplastic agents

that can potentially treat and prevent excessive scar formation. Some of them have

been used as "off-label" therapies, and others are still in the experimental phase

(e.g., interferon alpha (IFN-α), imiquimod, and transforming growth factor beta1 (TGF-

β1)). The use of IFN-α2b showed 18 % recurrence rate when applied to

post-surgical excised keloids. Imiquimod 5 % can lower recurrence rate on post-

shaved keloids to 37.5 % at 6-month and to 0 % at a 12-month follow-up period.

Transforming growth factor beta1 oligonucleotides have shown effective and long-

lasting inhibition of TGF-β-mediated scarring in-vitro as well as in animal models.

Daily injections of neutralizing antibodies against TGF-β1 and -β2 have shown

successful reductions in scarring. The authors concluded that latest discoveries in

the use of novel agents suggested therapeutic alternatives for the prevention of

recurrences of hypertrophic scars and post-excision keloid lesions.

Gold et al (2014) reviewed available data on methods for preventing and treating

cutaneous scarring. Relevant scientific literature was identified through a

comprehensive search of the MEDLINE database. Additional data and published



Page 16 of 50

studies were submitted for consideration by members of the International Advisory

Panel on Scar Management. One of the most significant advances in scar

management over the past 10 years has been the broader application of laser

therapy, resulting in a shift in status from an emerging technology to the forefront of

treatment. Accumulated clinical evidence also supports a greater role for 5-FU in

the treatment of hypertrophic scars and keloids, particularly in combination with

intralesional corticosteroids. The authors stated that encouraging data have been

reported for newer therapies, including bleomycin, onion extract-containing

preparations, imiquimod, and mitomycin C, although methodological limitations in

available studies merit consideration.

An UpToDate review on “Keloids and hypertrophic scars” (Goldstein and Goldstein,

2015) states that “Imiquimod -- A few small observational studies have reported

that postoperative use of imiquimod with daily or alternate day applications may

reduce the rate of recurrence of keloids. However, other studies have provided

conflicting results …. Other therapies that have been used for keloids include

intralesional bleomycin, mitomycin C, and topical imiquimod cream. There is

insufficient evidence to make definitive recommendations about these therapies

when used alone, although they may provide benefit when used after surgical

excision”.

Ledon et al (2013) provided a comprehensive review of current intralesional

treatment modalities for keloids and hypertrophic scars. These researchers

performed a PubMed search for literature pertaining to intralesional treatment

modalities for keloids and hypertrophic scars. References from retrieved articles

were also considered for review. These investigators noted that many intralesional

therapies for keloids and hypertrophic scars are currently available to physicians

and patients. Mechanisms of action and side effect profiles vary between these

agents, and new approaches to keloids and hypertrophic scars are frequently being

explored. The authors concluded that RCTs are needed to evaluate these new and

promising modalities fully.

Song (2014) noted that hypertrophic scars and keloids remain a challenge in

surgery. Although the bench to bedside conundrum remains, the science of

translational research calls for an even higher level of cooperation between the

scientist and the clinician for the impetus to succeed. The clinicians alerted the

possible theories in the pathogenesis of keloid formation, inter alia, the ischemia

theory, mast cell theory, immune theory, TGB-β interaction, mechanical theory, and



Page 17 of 50

the melanocyte stimulating hormone theory. All of the above presupposed a

stimulus that would result in an uncontrolled up-regulation of collagen and

extracellular matrix expression in the pathogenesis of the keloid. This bedside to

bench initiative, as in true science, realized more ponderables than possibilities. By

the same token, research into the epidermal-mesenchymal signaling, molecular

biology, genomics, and stem cell research holds much promise in the bench top

arena. To assess efficacy, many scar assessment scores exist in the literature.

The clinical measurement of scar maturity can aid in determining end-points for

therapeutics. Tissue oxygen tension and color assessment of scars by

standardized photography proved to be useful. In surgery, the use of dermal

substitutes holds some promise as these researchers surmised that quality scars

that arise from dermal elements, molecular and enzyme behavior, and balance.

Although a systematic review showed some benefit for earlier closure and healing

of wounds, no such review exists at this point in time for the use of dermal

substitutes in scars. Adipose-derived stem cell, as it pertains to scars, will hopefully

realize the potential of skin regeneration rather than by repair in which the

researchers were familiar with as well as the undesirable scarring as a result of

healing through the inflammatory response. The author concluded that

translational research will bear the fruit of coordinating bench to bedside and vice-

versa in the interest of progress into the field of regenerative healing that will benefit

the patient who otherwise suffers the myriad of scar complications.

Wat and associates (2014) provided evidence-based recommendations to guide

physicians in the application of intense pulsed light (IPL) devices for the treatment

of dermatologic disease. These investigators performed a literature search of the

CENTRAL (1991 to May 6, 2013), EMBASE (1974 to May 6, 2013), and MEDLINE

in-process and non-indexed citations and MEDLINE (1964 to present) databases.

Studies that examined the role of IPL in primary dermatologic disease were

identified, and multiple independent investigators extracted and synthesized data.

Recommendations were based on the highest level of evidence available. These

researchers found Level 1 evidence for the use of IPL for the treatment of

melasma, acne vulgaris, and telangiectasia; Level 2 evidence for the treatment of

lentiginous disease, rosacea, capillary malformations, actinic keratoses, and

sebaceous gland hyperplasia; and Level 3 or lower evidence for the treatment of

poikiloderma of Civatte, venous malformations, infantile hemangioma, hypertrophic

scars, superficial basal cell carcinoma, and Bowen's disease. The authors

concluded that IPL is an effective treatment modality for a growing range of



Page 18 of 50

dermatologic disease and in some cases may represent a treatment of choice. It is

typically well-tolerated. Moreover, they stated that further high-quality studies are

needed.

Goyal and Gold (2014) noted that keloids and hypertrophic scars remain one of the

more difficult treatment concerns for clinicians. A variety of therapies have been

used in the past with moderate success. On occasion, combination therapy has

been used to treat these lesions, in an attempt to lessen the symptoms of pain and

pruritus that often accompanies keloids and hypertrophic scars, as well as treating

the actual lesions themselves. These researchers introduced a novel triple

combination injection process in an attempt to further reduce the signs and

symptoms of these lesions. The combination includes 5-FU, triamcinolone

acetonide, and hyaluronidase. All 3 agents supposedly work in concert to treat

keloids and hypertrophic scars, and this was the first work at looking at these

medicines given together, at the same time, in a series of recalcitrant keloids and

hypertrophic scars. The authors concluded that the positive results warrant further

investigation and hope for those with keloids and hypertrophic scars.

Botulinum Toxin

In a systematic review, Prodromidou and colleagues (2015) examined available

evidence that support the use of botulinum toxin injections for the treatment or

prevention of hypertrophic scars in current clinical practice. A systematic review

searching the MEDLINE (1966 to 2014), Scopus (2004 to 2014), Popline (1974 to

2014), ClinicalTrials.gov (2008 to 2014) and Cochrane Central Register of

Controlled Trials (CENTRAL) (1999 to 2014) databases together with reference

lists from included studies was conducted. A total of 10 studies (255 patients) were

included. Of these, 123 patients were injected with botulinum toxin type A, 9

patients were offered botulinum toxin type B and the remaining 123 patients

represented the control groups. Significantly improved cosmetic outcomes were

observed among certain studies using the VAS (experimental group: median score

8.25 [range of 6 to 10]) versus control group: median score 6.38 [range of 2 to 9]; p

< 0.001) and the Stony Brook Scar Evaluation Scale (experimental group score: 6.7

versus control group score: 4.17; p < 0.001) assessments. However, the

methodological heterogeneity of the included studies, the lack of control group in

the majority of them, the use of subjective scales of measurement and the frequent

use of patient self-assessment precluded unbiased results. The authors concluded



http://ClinicalTrials.gov

Page 19 of 50

that current evidence does not support the usage of botulinum toxin; future RCTs

are needed in the field to reach firm conclusions regarding its place in current

clinical practice.

In a meta-analysis, Zhang and colleagues (2016) evaluated the effectiveness of

therapeutic BTX-A in the prevention of maxillofacial and neck scars. Information

came from the following electronic databases: Medline, PubMed, Cochrane Library,

and Embase (time was ended by August 31, 2015) to retrieve RCTs evaluating the

effect of the BTX-A for hypertrophic scar on the maxillofacial or neck. All languages

were included as long as they met the inclusion criteria. Effects of BTX-A were

evaluated by comparing the width of the scar, patient satisfaction, and VAS,

respectively. Pooled WMDs, pooled odds ratios (ORs), and 95 % CI were

calculated. A total of 9 RCTs (539 patients) were included. A statistically

significant difference in scar width was identified between the BTX-A group and

control group (non-BTX-A used) (WMD = -0.41, 95 % CI: -0.68 to -0.14, p = 0.003).

Statistically significant differences in patient satisfaction (OR = 25.76, 95 % CI: 2.58

to 256.67, p = 0.006) and VAS (WMD = 1.30, 95 % CI: 1.00 to 1.60, p < 0.00001)

were observed between the BTX-A group and control group. The authors

concluded that the findings of this meta-analysis suggested that BTX-A is more

effective and useful than non-BTX-A in eliminating hypertrophic scars from the

maxillofacial area and neck; BTX-A could improve the quality of the scars and meet

patients’ cosmetic requirements. Moreover, they stated that because there were

only a few studies, further clinical practice should be performed and larger

databases should be consulted to better determine the effectiveness of BTX-A

This study had several drawbacks: (i) the analysis conducted may not have taken

the differences in patient ages into account; they ranged from 3 months to 70

years old, (ii) the characteristics of patients in the included studies were not

homogeneous, (iii) only a few events were studied because of a lack of

evidence illustrating the results, and (iv) several of the studies were found to

have a high risk of performance or detection bias.

Liu and associates (2017) studied the effects of BTX-A on the treatment of

hypertrophic scars (HS) and the dose response of BTX-A. Hypertrophic scars

were harvested from the ears of 18 young adult New Zealand big-eared rabbits and

treated with BTX-A or triamcinolone acetonide (TAC) in-vivo experiment. The

hypertrophic index (HI) was measured by histological examination. Collagen fibrils

were checked by sirius red straining, and the cell nucleuses of fibroblasts were



Page 20 of 50

checked by Ki67. The HI of hypertrophic scars with BTX-A treatment was lower

than that with phosphate-buffered saline treatment (p < 0.05). Compared with the

TAC treatment group, the effectiveness of treatment with the middle dose of BTX-A

(1.0, 1.5 IU) had no significant difference, as shown by sirius red staining and

immunohistochemistry Ki67. The authors concluded that these findings showed

that BTX-A effectively improved the appearance HS and inhibited the formation of

collagen fibrils and fibroblasts in-vivo. They stated that middle dose BTX-A therapy

achieved similar effectiveness as TAC treatment, indicating that BTX-A might be

useful for inhibiting HS and worth investigating further.

Austin and associates (2018) noted that keloids and hypertrophic scars are

conditions of pathologic scarring characterized by fibroblast hyper-proliferation and

excess collagen deposition. These conditions significantly impact patients by

causing psychosocial, functional, and aesthetic distress. Current treatment

modalities have limitations. Clinical evidence indicated that botulinum toxin A (BoNT-

A) may prevent and treat keloids and hypertrophic scars. These researchers

investigated cellular pathways involved in BoNT-A therapeutic modulation of keloids

and hypertrophic scars. They searched PubMed, Embase, and Web of Science for

basic science articles related to botulinum toxin therapy, scarring, fibroblasts, keloids,

and hypertrophic scars. A total of 11 basic science articles involving keloids and

hypertrophic scars were reviewed. BoNT-A may reduce skin fibrosis by decreasing

fibroblast proliferation, modulating the activity of transforming growth factor-beta

(TGF-β), and reducing transcription and expression of pro-fibrotic cytokines in keloid-

derived and hypertrophic scar-derived dermal fibroblasts. BoNT-A may modulate

collagen deposition, but there is a paucity of evidence regarding specific mechanisms

of action. The authors concluded that BoNT-A has the potential to prevent or treat

pathologic scars in patients with a known personal or family history of keloids and

hypertrophic scars, which may improve patient psychosocial distress and reduce

clinic visits and health care costs. Variability in keloid and hypertrophic scar response

to BoNT-A may be due to inter- experiment differences in dosing, tissue donors, and

assay sensitivity.

Guida and colleagues (2018) noted that recent studies have highlighted new

botulinum neurotoxin (BoNT) applications in the field of dermatology. These

investigators reviewed current knowledge of BoNT use in dermatology; the

literature of the past 5 years was reviewed. These researchers described

interesting protocols of BoNT treatment for hyperhidrosis (HH), hypertrophic scars

and keloids, Raynaud phenomenon, facial flushing, oily skin, psoriasis, Hailey-



Page 21 of 50

Hailey disease, and cutaneous lesions like painful lesions and peri-orbital

syringomas. The authors concluded that several skin conditions eligible for BoNT

treatment have been described. After the wide application for HH treatment, scars

as well as vascular and inflammatory skin disorders, oily skin and cutaneous

lesions represent fields of application of BoNT. Moreover, these researchers stated

that further studies are needed to improve the knowledge of the connection

between BoNT and the cutaneous neuro-immune system and to better define

standard protocols of treatment.

Hao and co-workers (2018) stated that clinical observations indicate that botulinum

toxin type A (BTXA) can inhibit the growth and improve the eventual appearance of

hypertrophic scarring. However, the molecular mechanism remains unclear.

These researchers used human keloid fibroblasts to examine the molecular

mechanism of BTXA on hypertrophic scarring. Different concentrations of BTXA

(0.01, 0.1, 1, and 10 U/L) were used to treat keloid fibroblasts. Changes in cellular

morphology, viability, proliferation, cell cycle, and apoptosis were observed by

immuno-fluorescence, MTT assay, and flow cytometry. In addition, real-time qPCR

and Western blotting were used to explore the potential molecular mechanisms.

Keloid fibroblast viability decreased with increasing BTXA dose. After BTXA

treatment, the volume of keloid fibroblasts cells increased, but the nucleus of cells

shrunk. Long thin dendrites were formed as the concentration of BTXA increased.

Furthermore, the proliferation and S phase of keloid fibroblasts were inhibited by

BTXA. Matrix metalloproteinase (MMP)-1 and -2 RNA and protein showed high

expression, but TGF-β1 and MMP-9 showed low expression than the control. The

authors concluded that BTX A may promote the healing of scars by inhibiting the

proliferation of keloid fibroblasts and regulating the expression of TGF-β1, which

could affect the expression of MMP-1 and MMP-2. They stated that the findings of

this study provided theoretical support for the clinical application of BTXA to control

hypertrophic scarring.

Calcium Antagonists

Verhiel et al (2015) provided a comprehensive evidence-based review of current

evidence on mechanism of action, effectiveness, and adverse events of calcium

antagonists in treatment of hypertrophic scars and keloids. A Cochrane Library and

PubMed search was performed for the literature pertaining to treatment with

calcium antagonists in pathological scars. Articles were categorized into 2 groups:

(i) mechanism of action or effectiveness and (ii) adverse events. A total of 6 in-



Page 22 of 50

vitro studies were included in the first subgroup. Calcium antagonists have been

found to reduce extra cellular matrix production, induce procollagenase synthesis,

and inhibit interleukin-6, vascular endothelial growth factor, and proliferation of

fibroblasts; 8 studies with a median level of evidence of 3.5 (range of 2 to 4) were

included in the second category. A good efficacy with no major side effects was

reported for calcium antagonists. The authors concluded that important

methodological shortcomings of the available literature were identified. They stated

that interesting results have been reported, but further large scale, high-quality

studies are needed to optimally evaluate the effectiveness of treatment with calcium

antagonists.

Wang et al (2016) evaluated the effectiveness of verapamil in preventing and

treating keloid and hypertrophic scars. Searches were conducted in Medline,

EMbase and Cochrane databases from 1974 to January 2015. The selection of

articles was limited to human subjects. A total of 5 RCTs or cluster-randomized

trials or controlled clinical trials (CCTs) comparing the effectiveness of verapamil

with conventional treatments were identified. The results showed that verapamil

could improve keloid and hypertrophic scars, and was not significantly different

from conventional corticosteroid injections. Few adverse effects were observed.

However, this result should be considered carefully, as most of the included

studies have a high risk of bias because of issues with randomization, allocation

concealment, blinding, incomplete outcomes and selective reporting. The authors

concluded that verapamil could act as an effective alternative modality in the

prevention and treatment of keloid and hypertrophic scars; however, they stated

that more high-quality, multiple-center, large-sample RCTs are needed to define the

role of verapamil in preventing and treating keloid and hypertrophic scars.

In a double-blind RCT with a paired split-scar design, Danielsen et al (2016)

compared verapamil and triamcinolone for prevention of keloid recurrence after

excision. Calcium channel blocking activity of verapamil in keloid cells was

explored. One keloid was excised per subject and each wound half randomized to

receive intralesional injections of triamcinolone (10 mg/ml) or verapamil (2.5 mg/ml)

at monthly intervals (4 doses). Interim analysis was performed after 14 subjects

were recruited. Survival analysis demonstrated significantly higher keloid

recurrence with verapamil compared to triamcinolone 12 months post-surgery (log-

rank test, p = 0.01) and higher overall risk of recurrence with verapamil (hazard ratio

[HR] 8.44, 95 % CI: 1.62 to 44.05). The study was terminated early according to

the stopping guideline (p < 0.05). The authors concluded that verapamil is safe but



Page 23 of 50

not as effective as triamcinolone in preventing keloid recurrence after excision.

They stated that further study is needed to determine if clinical response to

verapamil is linked to modulation of intracellular calcium.

Li and Jin (2016) stated that keloids and hypertrophic scars are the most common

types of pathological scarring. Traditionally, keloids have been considered as a

result of aberrant wound healing, involving excessive fibroblast participation that is

characterized by hyalinized collagen bundles. However, the usefulness of this

characterization has been questioned. In recent years, studies have reported the

appropriate use of verapamil for keloids and hypertrophic scars. Searches were

conducted on the databases Medline, Embase, Cochrane, PubMed, and China

National Knowledge Infrastructure from 2006 to July 2016. State12.0 was used for

literature review, data extraction, and meta-analysis. Treatment groups were

divided into verapamil and non-verapamil group. Non-verapamil group included

steroids and intense pulsed light (IPL) therapy. Total effective rates included cure

rate and effective rate. Cure: skin lesions were completely flattened, became soft

and symptoms disappeared. Efficacy: skin lesions subsided, patient significantly

reduced symptoms. Inefficient definition of skin was progression free or became

worse. Random-effects model was used for the meta-analysis. A total of 6 studies

that included 331 patients with keloids and hypertrophic scars were analyzed.

Analysis of the total effective rate of skin healing was performed. The total

effective rates in the 2 groups were 54.07 % (verapamil) and 53.18 % (non-

verapamil), respectively. The meta-analysis showed that there was no difference

between the 2 groups. These researchers also compared the adverse reactions

between the verapamil treatment group and the steroids treatment group in 2

studies, and the result indicated that the verapamil group showed less adverse

reactions. The authors concluded that there were no differences between the

application of verapamil and non-verapamil group in keloids and hypertrophic scars

treatment. These investigators stated that verapamil could act as an effective

alternative modality in the prevention and treatment of keloid and hypertrophic

scars; a larger number of studies are needed to confirm their conclusion.

This study had several drawbacks: (i) articles and data were not too many

according to the inclusion criteria; this probably caused publication bias, (ii)

uncontrolled confounding factors and selection bias resulted in some

heterogeneity in the study, and (iii) only articles published and written in

English and Chinese were included this meta-analysis, which might have

resulted in some degree of publication bias.



Page 24 of 50

Anti-Vascular Endothelial Growth Factor Therapy (e.g., Bevacizumab)

Kwak and colleagues (2016) noted that hypertrophic scarring is a pathological

condition that occurs after trauma or surgery. Angiogenesis occurs more often with

hypertrophic scarring than with normotrophic scarring. The regulation of

angiogenesis is one of the key factors in hypertrophic scar management. Vascular

endothelial growth factor (VEGF) is an essential factor in the angiogenetic

response. These researchers examined if decreasing the level of VEGF is effective

for treating hypertrophic scarring. A total of 10 8-week-old female New Zealand

white rabbits were included; 4 defects were created on each ear by using a 6-mm

punch. Bevacizumab was administered in 1 ear and normal saline was

administered in the other ear. Treatment was administered starting on day 2, every

2 days, until day 14. The levels of VEGF were measured using enzyme-linked

immunosorbent assay on day 10 and histologic results were analyzed on day 40.

Bevacizumab induced-defects showed less hypertrophic scarring when compared

with the control group as measured by the scar elevation index (SEI) and loose

collagen arrangement. The SEI in the experimental group was 1.89 ± 0.13,

compared to 1.99 ± 0.13 in the control group (n = 30, p = 0.005). Additionally, the

VEGF level was lower (38.72 ± 11.03 pg versus 82.50 ± 21.64 pg, n = 10, p =

0.001) and fewer vessels existed (8.58 ± 0.76 versus 7.2 ± 1.20, n = 10, p =

0.007). The authors concluded that preventing excessive angiogenesis is effective

for preventing scar formation, especially with hypertrophic scarring. Moreover, they

stated that although bevacizumab reduces scar formation, it does have adverse

effects. No research on the effect of local injection or topical application of

bevacizumab to scars has been published. They stated that further research

should be performed in-vivo to ensure the use of bevacizumab without adverse

effects and to reveal the mechanisms underlying its effect.

Autologous Fat Grafting

Silva and colleagues (2016) noted that since the 1980s, the use of autologous fat

grafting has been growing in plastic surgery. Recently, this procedure has come to

be used as a treatment for keloids and hypertrophic scars mainly due to the lack of

satisfactory results with other techniques. So far, however, it lacks more consistent

scientific evidence to recommend its use. These investigators reviewed the

evidence of autologous fat grafting for the treatment of keloids and hypertrophic

scars. They performed a review in the PubMed database using the keywords "fat

grafting and scar", "fat grafting and keloid scar" and "fat grafting and hypertrophic



Page 25 of 50

scar". Inclusion criteria were articles written in English and published in the last 10

years, resulting in 15 studies. These articles indicated that autologous fat grafting

performed at sites with pathological scars led to a reduction of the fibrosis and pain,

an increased range of movement in areas of scar contraction, an increase in their

flexibility, resulting in a better quality of scars. The authors concluded that current

evidence suggested that autologous fat grafting for the treatment of keloids and

hypertrophic scars is associated with a better quality of scars, leading to esthetic

and functional benefits. However, they noted that this review has limitations and

these findings should be treated with reservations, since they mostly came from

studies with low levels of evidence (9 of the 15 articles were classified as cases

series (evidence level: IV). They stated that new studies with the strongest level of

evidence (randomized and controlled clinical trials, prospective cohort studies, and

comparative studies with control groups) are needed to elucidate some of the gaps

in our knowledge concerning the role of autologous fat grafting in pathological scars

(e.g., the standardization of surgical indication, more prolonged post-operative

monitoring assessment of late-onset results, the systematization of conduct and

proof of the role of adipose-derived stem cell in the promotion of cicatricial

improvement).

Pressure Therapy

Ai and colleagues (2017) stated that although pressure therapy (PT) represents the

standard care for prevention and treatment of HS from burns, its practice is largely

based on empirical evidence and its effectiveness remains controversial. These

researchers examined the effect of PT for HS; they performed a systematic review

and meta-analysis. Several electronic databases were screened to identify related

RCTs; 12 RCTs involving 710 patients with 761 HS resulting from burn injuries

were included. Compared with non/low-PT, cases treated with PT (15 to 25 mmHg)

showed significant differences in Vancouver Scar Scale score (MD = -0.58, 95 % CI: -

0.78 to -0.37), thickness (SMD = -0.25, 95 % CI: -0.40 to -0.11), brightness (MD

= 2.00, 95 % CI: 0.59 to 3.42), redness (MD = -0.79, 95 % CI: -1.52 to -0.07),

pigmentation (MD = -0.16, 95 % CI: -0.32 to -0.00) and hardness (SMD = -0.65, 95

% CI: -1.07 to -0.23). However, there was no difference in vascularity (MD = 0.03,

95 % CI: -0.43 to 0.48). The authors concluded that the findings of this meta-

analysis indicated that patients with HS who were managed with PT (15 to 25 mmHg)

showed significant improvements. However, due to limitations, more large

and well-designed studies are needed to confirm these findings and the side-effects



Page 26 of 50

of the PT may also need to be evaluated. They stated that future investigations

should ensure adequate randomization, concealment of allocation, blinding of

patients and outcome assessors and descriptions of withdrawals and losing.

This study had several drawbacks: (i) the results may be influenced by the small

number of included studies, the limited sample-size and inconsistent clinical

outcomes of each study, (ii) due to insufficient data, the study did not consider

the percentage of total body surface area (%TBSA), burn degree and burn site

although the different %TBSA, burn degree and burn site may have varying

efficacy, (iii) since long-term follow-up studies were rare, the study failed to

analyze the prospective efficacy of PT, (iv) none of the included studies studied

adverse effects and these researchers were unable to assess the safety of PT,

and (v) this analysis suffered in quality of included studies because most of the

studies did not describe the allocation concealment and blinding method,

which may exaggerate the treatment effects, especially in subjective outcomes.

Extracorporeal Shock Wave Therapy

Zhao and colleagues (2018) examined the effects of radial extracorporeal shock

wave therapy (rESWT) on scar characteristics and TGF-β1/Smad signaling to

explore a potential modality for the treatment of hypertrophic scars (HS). The HS

model was generated in rabbit ears, then rabbits were randomly divided into 3

groups: Lower (L)-ESWT [treated with rESWT with lower energy flux density (EFD)

of 0.1 mJ/mm2], higher (H)-ESWT (treated with a higher EFD of 0.18 mJ/mm2) and

the sham ESWT group (S-ESWT; no ESWT treatment). Scar characteristics

(wrinkles, texture, diameter, area, volume of elevation, hemoglobin and melanin)

were assessed using the Antera 3D system. The protein and mRNA expression of

TGF-β1, Smad2, Smad3 and Smad7 was assessed by enzyme-linked

immunosorbent assay (ELISA) and reverse transcription-quantitative polymerase

chain reaction (PCR), respectively. The Antera 3D results indicated that wrinkles

and hemoglobin of the HS were significantly improved in both of the rESWT groups

when compared with the S-ESWT group. However, these changes appeared much

earlier in the L-ESWT group than the H-ESWT. Scar texture was also improved in

the L-ESWT group. However, rESWT did not influence HS diameter, area, volume

of elevation or melanin levels. rESWT had no effect on TGF-β1 or Smad7

expression in either of rESWT groups. Although no difference was observed in

Smad2 mRNA expression in the L-ESWT group, the Smad3 mRNA and protein

expression significantly decreased when compared with the H-ESWT and S-ESWT



Page 27 of 50

groups. By contrast, Smad2 and Smad3 mRNA expression were up-regulated in

the H-ESWT group. These results demonstrated that rESWT with 0.1 mJ/mm2

EFD improved some characteristics of the HS tissue. Down-regulation of Smad3

expression may underlie this inhibitory effect. The authors concluded that inhibition

of the TGF-β1/Smad signal transduction pathway may be a potential therapeutic

target for the management of HS.

Cui and associates (2018) noted that ESWT considerably improves the appearance

and symptoms of post-burn hypertrophic scars (HTS). However, the mechanism

underlying the observed beneficial effects is not well understood. These

researchers examined the mechanism underlying changes in cellular and molecular

biology that is induced by ESWT of fibroblasts derived from scar tissue (HTSFs).

They cultured primary dermal fibroblasts derived from human HTS and exposed

these cells to 1,000 impulses of 0.03, 0.1, and 0.3 mJ/mm². At 24 hours and 72

hours after treatment, real-time PCR and Western blotting were used to detect

mRNA and protein expression, respectively, and cell viability and mobility were

assessed. While HTSF viability was not affected, migration was decreased by

ESWT; TGF-β1 expression was reduced and alpha smooth muscle actin (α-SMA),

collagen-I, fibronectin, and twist-1 were reduced significantly after ESWT.

Expression of E-cadherin was increased, while that of N-cadherin was reduced.

Expression of inhibitor of DNA binding 1 and 2 was increased. The authors

concluded that suppressed epithelial-mesenchymal transition might be responsible

for the anti-scarring effect of ESWT, and has potential as a therapeutic target in the

management of post-burn scars.

Growth Hormone-Releasing Peptide 6

Fernandez-Mayola and associates (2018) stated that HTS and keloids are forms of

aberrant cutaneous healing with excessive extracellular matrix (ECM) deposition.

Current therapies still fall short and cause undesired effects. These investigators

evaluated the ability of growth hormone releasing peptide 6 (GHRP6) to both

prevent and reverse cutaneous fibrosis and to acquire the earliest proteome data

supporting GHRP6's acute impact on aesthetic wound healing. Two independent

sets of experiments addressing prevention and reversion effects were conducted

on the classic HTS model in rabbits. In the prevention approach, the wounds were

assigned to topically receive GHRP6, triamcinolone acetonide (TA), or vehicle (1 %

sodium carboxy methylcellulose [CMC]) from day 1 to day 30 post-wounding. The

reversion scheme was based on the infiltration of either GHRP6 or sterile saline in



Page 28 of 50

mature HTS for 4 consecutive weeks. The incidence and appearance of HTS were

systematically monitored. The sub-epidermal fibrotic core area of HTS was

ultrasonographically determined, and the scar elevation index was calculated on

hematoxylin/eosin-stained, microscopic digitized images. Tissue samples were

collected for proteomics after 1 hour of HTS induction and treatment with either

GHRP6 or vehicle. GHRP6 prevented the onset of HTS without the untoward

reactions induced by the 1st-line treatment TA; however, it failed to significantly

reverse mature HTS. The authors concluded that the findings of these preliminary

proteomic study suggested that the anti-fibrotic preventing effect exerted by

GHRP6 depended on different pathways involved in lipid metabolism, cytoskeleton

arrangements, epidermal cells' differentiation, and ECM dynamics. They stated

that these results enlightened the potential success of GHRP6 as one of the

incoming alternatives for HTS prevention.

Hyperbaric Oxygen Therapy

Ren and colleagues (2018) examined the influence of hyperbaric oxygen (HBO) on

scar formation in rabbit ears. A total of 20 New Zealand rabbits were selected to

establish the hypertrophic scar model on the ears. The rabbits were randomly

divided into control group and experimental group (7d, 14d, 21d, and 28d group

according to different HBO treatment days), each experimental group received

HBO treatment after the operation at the same time every day for 1 hour. After the

day 29, the scars were collected. Histo-morphological change in scars was

observed by hematoxylin-eosin staining, Masson staining, and transmission

electrical microscope. The expression of bax, bcl-2, and the cell apoptosis rate was

detected by immuno-histochemical method. Both number of fibroblast and amount

of collagen fibrils in experimental group were significantly reduced compared with

those in control group. In Masson staining, arrangement of collagen fibrils in

experimental group was much more irregular and coarse than control groups. HI

value can be found much smaller in the experimental groups than the control (p <

0.05). Among the 4 experimental groups, there was significant difference among

7d, 14d, and 21d groups (p < 0.05), while there was no difference between 21d and

28d groups (p > 0.05). Expression of Bax could be detected up-regulated in

experimental group (p < 0.05). While the expression of Bcl-2 was detected

significantly down-regulated in experimental group than that in control group (p <

0.05). Compared with the 7d group, the expression of Bax and Bcl-2 had

significant difference in 14d group (p < 0.05), and the expression of this 2 factors in

21d group had significant difference comparing with 14d group(p < 0.05),but there



Page 29 of 50

was no significant difference between 28d group and 21d group(p > 0.05).

Significant difference of cell apoptosis rate can be detected between the

experimental groups and the control group (p < 0.05). Among the 4 experimental

groups, there was significant difference among 7d, 14d, and 21d groups (p < 0.05),

while there was no difference between 21d and 28d groups (p > 0.05). The authors

concluded that HBO can up-regulate bax/bcl-2 value, increase the cell apoptosis

rate, and inhibit the early hypertrophic scar in rabbit ears.

Mesenchymal Stem Cell and Miscellaneous Investigational Treatments

Fan and associates (2018) noted that Cesarean delivery has already become a

very common method of delivery around the world, especially in low-income

countries. Hypertrophic scars and wound infections have affected younger mothers

and frustrated obstetricians for a long time. Mesenchymal stem cells (MSCs) have

strong potential for self-renewal and differentiation to multi-lineage cells. Previous

studies have demonstrated that MSCs are involved in enhancing diabetic wound

healing. Thus, this study is designed to examine the safety and efficacy of MSCs in

the treatment of Cesarean section skin scars. This trial is a prospective,

randomized, double-blind, placebo-controlled, single-center trial with 3 parallel

groups. A total of 90 eligible participants will be randomly allocated to placebo, low-

dose (transdermal hydrogel MSCs; 3 × 106 cells) or high-dose (transdermal

hydrogel MSCs; 6 × 106 cells) groups at a 1:1:1 allocation ratio according to a

randomization list, once-daily for 6 consecutive days. Study duration will last for 6

months, comprising a 1 week run-in period and 24 weeks of follow-up. The primary

aim of this trial is to compare the difference in Vancouver Scar Scale rating among

the 3 groups at 6th month. Adverse events (AEs), including severe and slight signs

or symptoms, will be documented in case report forms. The authors concluded that

this trial is the first investigation of the potential for therapeutic use of MSCs for the

management of women's skin scar after Cesarean delivery.

In a review on “Recent understandings of biology, prophylaxis and treatment

strategies for hypertrophic scars and keloids”, Lee and Jang (2018) listed the

following as emerging therapies: botulinum toxin, fat grafting, interferons, MSCs,

and transforming growth factor-beta. The authors concluded that although

encouraging results of molecular- or cytokine-targeting therapies are being

continuously reported, current prophylaxis and treatment strategies still mainly



Page 30 of 50

focus on decreasing inflammatory processes. They stated that further

understanding of the mechanisms underlying excessive scarring is needed to

develop more effective prophylaxis and treatment strategies.

Micro-Needling for the Treatment of Hypertrophic Scars and Keloids

Dogra and colleagues (2014) evaluated the safety and effectiveness of micro-

needling treatment for atrophic facial acne scars. A total of 36 patients (26 females,

10 males) with post-acne atrophic facial scars underwent 5 sittings of derma-roller

under topical anesthesia at monthly intervals. Objective evaluation of improvement

was performed by recording the acne scar assessment score at baseline and

thereafter at every visit. Pre- and post-treatment photographs were compared, and

improvement was graded on quartile score. Final assessment was performed 1

month after the last sitting. Patients were asked to grade the improvement in acne

scars on VAS (0 to 10 point scale) at the end of study. Of 36 patients, 30

completed the study. The age group ranged from 18 to 40 years, and all patients

had skin phototype IV or V. There was a statistically significant decrease in mean

acne scar assessment score from 11.73 ± 3.12 at baseline to 6.5 ± 2.71 after 5

sittings of derma-roller. Investigators' assessment based on photographic

evaluation showed 50 to 75 % improvement in majority of patients. The results on

VAS analysis showed "good response" in 22 patients and "excellent response" in 4

patients, at the end of study. The procedure was well-tolerated by most of the

patients, and chief complications noted were post-inflammatory hyperpigmentation

in 5 patients and tram-trek scarring in 2 patients. The authors concluded that

micro-needling with derma-roller is a simple and cheap, means of treatment

modality for acne scars re-modulation with little downtime, satisfactory results and

peculiar side effects in Asian skin type. The findings of this small (n = 36)

uncontrolled study need to be validated by well-designed studies.

In a retrospective study, Chandrashekar et al (2014) assessed the safety and

effectiveness of micro-needling fractional radiofrequency in the treatment of acne

scars. A total of 31 patients of skin types III to V with moderate and severe facial

acne scarring received 4 sequential fractional RF treatments over a period of 6

months with an interval of 6 weeks between each session. Goodman & Baron's

acne scar grading system was used for assessment by a side by side comparison

of pre-operative and post-operative photographs taken at their first visit and at the

end of 3 months after the last session. Estimation of improvement with Goodman

and Baron's Global Acne Scarring System showed that by qualitative assessment



Page 31 of 50

of 31 patients with grade 3 and grade 4 acne scars, 80.64 % showed improvement

by 2 grades and 19.35 % showed improvement by 1 grade. Quantitative

assessment showed that 58 % of the patients had moderate, 29 % had minimal, 9

% had good and 3 % showed very good improvement. Adverse effects were

limited to transient pain, erythema, edema and hyperpigmentation. The authors

concluded that micro-needling fractional RF is effective for the treatment of

moderate and severe acne scars. The findings of this small (n = 31) retrospective

study need to be validated by well-designed studies.

Furthermore, UpToDate reviews on “Keloids and hypertrophic scars” (Goldstein

and Goldstein, 2015), “Management of keloid and hypertrophic scars following burn

injuries” (Gauglitz, 2015), and “Management of acne scars” (Saedi and Uebelhoer,

2015) do not mention micro-needling as a therapeutic option.

Ramult and colleagues (2018) noted that patients who suffer from scars or wrinkles

have several therapeutic options to improve the appearance of their skin. The

available treatment modalities that provide desirable results are often overtly

invasive and entail a risk of undesirable adverse effects. Micro-needling has

recently emerged as a non-ablative alternative for treating patients who are

concerned with the aesthetic changes that result from injury, disease or ageing. In

a systematic review, these investigators evaluated the current evidence in the

literature on micro-needling. A systematic literature review was performed by

searching the electronic databases PubMed and Google Scholar. The reviewed

articles were analyzed and compared on study design, therapeutic protocol,

outcome parameters, efficacy measurement and results to evaluate the strength of

the current evidence. Micro-needling was examined in experimental settings for its

effects on atrophic acne scars, skin rejuvenation, hypertrophic scars, keloids, striae

distensae, androgenetic alopecia, melasma and acne vulgaris. Several clinical

trials used randomization and single-blind design to strengthen the validity of the

study outcome. Micro-needling showed noteworthy results when used on its own

and when combined with topical products or RF. When compared with other

treatments, it showed similar results but was preferred due to minimal AEs and

shorter down-time. The authors concluded that this systematic review positioned

micro-needling as a safe and effective therapeutic option for the treatment of scars

and wrinkles. These researchers stated that the current literature show some

methodological shortcomings, and further research is needed to truly establish micro-

needling as an evidence-based therapeutic option for treating scars, wrinkles and

other skin conditions.



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Fractional Ablative laser for the Treatment of Burn Scars

Sheridan et al (1997) stated that hypertrophic scarring is a major source of

morbidity in patients with burns. The physiologic characteristics are poorly

understood, but increased neo-vascularity is typically seen in those wounds

destined to become hypertrophic. These investigators theorized that ablation of the

developing neo-vasculature may favorably influence the development of the

hypertrophic scar. In a pilot study, these researchers established the practicality

and safety of tunable dye laser neo-vessel ablation at 585 nm; 10 sites of evolving

hypertrophic scar in 9 children were treated with a series of 450 msec 6.75 J/cm2

pulses at 585 nm. Although all children had the expected transient post-treatment

purpura, no pain, ulceration, pruritus, or worsening of the lesions was seen. The

authors concluded that this technique appeared safe and was worthy of continuing

investigation. They stated that investigations with higher fluences and multiple

treatments were in progress.

Parrett and Donelan (2010) noted that hypertrophic scarring after partial-thickness

burns is common, resulting in raised, erythematous, pruritic, and contracted scars.

Treatment of hypertrophic scars, especially on the face, is challenging and has high

failure rates. Excisional treatment has morbidity and can create iatrogenic

deformities. After an extensive experience over 10 years with laser therapy for the

treatment of difficult scars, the pulsed dye laser (PDL) has emerged as a successful

alternative to excision in patients with hypertrophic burn scars. Multiple studies

have shown its ability to decrease scar erythema and thickness while significantly

decreasing pruritus and improving the cosmetic appearance of the scar. The

authors concluded that PDL should become an integral part of the management of

burn scarring and would significantly decrease the need for excisional surgery.

This was a review; it did not provide clinical data to support its claim.

Hultman et al (2014) presented the largest study to-date that examined long-term

impact of laser therapies, a potentially transformative technology, on scar

remodeling. These investigators conducted a prospective, before-after cohort study

in burn patients with hypertrophic scars; PDL was used for pruritus and erythema;

fractional CO2 laser was used for stiffness and abnormal texture. Outcomes

included Vancouver Scar Scale (VSS), which documents pigmentation, erythema,

pliability, and height, as well as University of North Carolina "4P" Scar Scale

(UNC4P), which rates pain, pruritus, paresthesias, and pliability. A total of 147 burn

patients (mean age of 26.9 years; total body surface area [BSA], 16.1 %) received



Page 33 of 50

415 laser sessions (2.8 sessions/patient), 16 months (median) after injury, including

PDL (n = 327) and CO2 laser (n = 139). Laser treatments produced rapid,

significant, and lasting improvements in hypertrophic scar. Provider-rated VSS

dropped from 10.43 [standard deviation (SD) 2.37] to 5.16 (SD 1.92), by the end of

treatments, and subsequently decreased to 3.29 (SD 1.24), at a follow-up of 25

months. Patient-reported UNC4P fell from 5.40 (SD 2.54) to 2.05 (SD 1.67), after

the 1st year, and further decreased to 1.74 (SD 1.72), by the end of the study

period. The authors concluded that for the first time, ever, in a large prospective

study, laser therapies have been shown to dramatically improve both the signs and

symptoms of hypertrophic burn scars, as measured by objective and subjective

instruments. They stated that laser treatment of burn scars represented a

disruptive innovation that could yield results not previously possible and may

displace traditional methods of operative intervention.

Blome-Eberwein et al (2016) conducted a prospective study of fractional CO2 laser

treatment of mature burn scars, comparing objective and subjective scar

measurements evaluating at least 1 treatment and 1 control scar on the same

patient pre- and post-treatments. After institutional review board approval, burn

survivors with mature blatant burn scars were invited to enter the study. A series of

3 fractional CO2 laser treatments was performed in an office-setting, using topical

anesthetic cream, at 40 to 90 mJ, 100 to 150 spots per cm. Subjective and

objective measurements of scar physiology and appearance were performed before

and at least 1 month after the treatment series on both the treated and the control

scar. A total of 80 scars, 48 treatment and 32 control scars, were included in the

study. Treatment pain score averaged at 4.7/10 during and at 2.4/10 5 minutes

after the treatment. All treated scars showed improvement. Objectively measured

thickness, sensation, erythema, and pigmentation improved significantly in the

treated scars (p = 0.001, 0.001, 0.004, and 0.001). Elasticity improved, but without

statistical significance; VSS assessments by an independent observer improved

from 8 to 6; patient self-reported pain and pruritus remained unchanged in both

groups. The authors concluded that fractional CO2 laser treatment is a promising

entity in the treatment of burn scars; these findings showed significant differences

in objective measurements between the treated scars and the untreated control

scars over the same time period. In scar treatment studies, the patient/observer

and VSS may not be sensitive enough to detect outcome differences.



Page 34 of 50

Tao et al (2018) stated that burn scars cause cosmetic disfigurement and

psychosocial distress. These researchers presented 2 Fitzpatrick phototype (FP) III

patients with burn scars successfully treated with combined PDL and non-ablative

fractional lasers (NAFL). Case 1: A 30-year old, FP III woman with a history of a 2nd-

degree burn injury to the bilateral arms and legs affecting 30 % BSA presented for

cosmetic treatment. The patient received 3 treatments with 595 nm PDL (7 mm, 8 J,

6 ms), 6 with the 1,550 nm erbium:glass laser (30 mJ, 14 % density, 4 to 8

passes) and 5 with the 1,927 nm thulium laser (10 mJ, 30 % density, 4 to 8

passes). Treated burn scars improved significantly in thickness, texture and color.

Case 2: A 33-year old, FP III man with a history of a 2nd-degree burn injury of the

left neck and arm affecting 7 % BSA presented for cosmetic treatment. The patient

received 2 treatments with 595 nm PDL (5 mm, 7.5 J, 6 ms), 4 with the 1,550 nm

erbium:glass laser (30 mJ, 14 % density, 4 to 8 passes) and 2 with the 1,927 nm

thulium laser (10 mJ, 30 % density, 4 to 8 passes). The burn scars became

thinner, smoother and more normal in pigmentation and appearance. These

patients' burn scars were treated with a combination of PDL and NAFL (2

wavelengths). The PDL targets scar hyper-vascularity, the 15,50 nm erbium:glass

stimulates collagen re-modelling and the 1,927 nm thulium targets epidermal

processes, particularly hyper-pigmentation. They stated that this combination

addressed scar thickness, texture and color with a low side effect profile and was

particularly advantageous in patients at higher risk of post-procedure

hyperpigmentation. The authors concluded that their cases suggested the NAFL

1,550 nm erbium:glass/1,927 nm thulium device was effective and well-tolerated for

burn scar treatment in darker skin types and could be used in combination with the

595-nm PDL and topical tacrolimus. The thulium laser specifically addressed

hyper-pigmentation, which was advantageous in patients with skin of color who

were more prone to developing PIH. Moreover, they stated that further studies are

needed to optimize settings and establish treatment guidelines.

Zuccaro et al (2018) noted that treatment with laser therapy has the potential to

greatly improve hypertrophic scarring in individuals who have sustained burn

injuries. More specifically, recent research has shown the success of using PDL

therapy to help reduce redness and post-burn pruritus and using ablative fractional

CO2 laser therapy to improve scar texture and thickness. This study described the

authors’ early experience using laser therapy in their pediatric burn program and

detailed their specific therapeutic approach when using each laser individually and

in combination during the same procedure. A retrospective before-after study of

patients with hypertrophic burn scars who were treated with laser therapy at the



Page 35 of 50

authors’ pediatric institution was performed. A total of 125 patients were treated

over a total of 289 laser sessions with more than 50 % of patients under the age of

5 years at the 1st treatment. The majority of procedures were performed using

both the PDL and CO2 lasers in combination. Before-after VSS scores decreased

from 7.37 (SD, 2.46) to 5.76 (SD, 2.29) after a single treatment. The authors

concluded that the results obtained from this study supported the use of laser

therapy to improve hypertrophic burn scars in the pediatric population. Moreover,

they stated that rigorous randomized controlled trials (RCTs) are needed to confirm

the effectiveness of this therapy.

Rodriguez-Menocal et al (2018) stated that hypertrophic scarring is a fibro-

proliferative process that occurs following a 3rd-degree dermal burn injury,

producing significant morbidity due to persistent pain, itching, cosmetic

disfigurement, and loss of function due to contractures. Ablative fractional lasers

have emerged clinically as a fundamental or standard therapeutic modality for

hypertrophic burn scars. Yet the examination of their histopathological and

biochemical mechanisms of tissue remodeling and comparison among different

laser types has been lacking. In addition, deficiency of a relevant animal model

limits the ability to gain a better understanding of hypertrophic scar

pathophysiology. To evaluate the effect of ablative fractional lasers on hypertrophic

3rd-degree burn scars, these researchers have developed an in-vivo red Duroc

porcine model; 3rd-degree burn wounds were created on the backs of animals, and

burn scars were allowed to develop for 70 days before treatment. Scars received

treatment with either CO2 or erbium: yttrium aluminum garnet (YAG) ablative

fractional lasers. These investigators describe the effect of both lasers on

hypertrophic third-degree burn scars in red Duroc pigs. In this report, these

researchers found that Er:YAG had improved outcomes versus fractional CO2.

Molecular changes noted in the areas of dermal remodeling indicated that matrix

metalloproteinase 2, matrix metalloproteinase 9, and Decorin may play a role in this

dermal remodeling and accounted for the enhanced effect of the Er:YAG laser.

They demonstrated that ablative fractional laser treatment of burn scars could lead

to favorable clinical, histological, and molecular changes. The authors concluded

that the findings of this study provided support that hypertrophic 3rd-degree burn

scars could be modified by fractional laser treatment.

International scar management guidelines (Monstrey, et al., 2014) included laser

therapy among "Investigational treatments and those with less supporting

evidence."



Page 36 of 50

An UpToDate review on hypertrophic scars and keloids following burn injuries

(Gauglitz, 2019) found that "laser treatment (particularly fractional ablation type),

often in combination with local flap design and/or the application of intralesional

agents, is increasingly being advocated and appears to show promise, though

efficacy measured by objective parameters varies between studies. Patient

satisfaction is nevertheless high. Further randomized controlled studies are

needed." Furthermore, UpToDate reviews on “Overview of the management of the

severely burned patient” (Gauglitz and Williams, 2019) and “Treatment of minor

thermal burns” (Wiktor and Richards , 2019) do not mention laser / fractional

ablative laser as a therapeutic option.

Intralesional Fiber Laser Device for the Treatment of Keloids

Li and colleagues (2019) presented the findings of a study conducted with a 1,470-

nm diode laser using an intralesional optical fiber device for the treatment of

inflamed keloid scars. These researchers examined its efficacy as a novel

alternative method to decrease keloid infection and inflammation. Participants who

underwent 1,470-nm laser treatment from February 2016 to February 2018 at the

plastic and reconstructive surgery department of the Shanghai Ninth People's

Hospital Affiliated to Shanghai Jiao Tong University with keloid accompanying

serious local infection and fester were included. Subjects took curative effect

evaluation before and 1 year after the treatment. The test items included infection

frequency in each year; pain (by VAS); itch (by VAS); quality of life (QOL), using

QOL scale; and blood supply, using PeriCam PSI. A total of 19 patients (mean age

of 35.21 years, range of 11 to 66) with history of inflamed keloids with episodes of

infection or abscess were enrolled. Patients underwent to a 1,470-nm laser therapy

for average of 1.16 times. After treatment, infection frequency and blood supply in

keloids were reduced (p < 0.001). Pain, itching, and QOL were improved (p < 0.001).

The authors concluded that the findings of the present study showed that 1,470-

nm fiber laser treatment could improve inflamed keloids fairly well by decreasing

inflammation, and a relative stabilization of collagen composition. Thus, it is an

effective minimally invasive scar therapy, but further studies with more subjects and

long-term follow-up are needed to confirm these preliminary findings.

Losartan Ointment for the Treatment of Hypertrophic Scars and Keloids



Page 37 of 50

In a placebo-controlled, single-blind, pilot study (Hedayatyanfard and associates,

2018) on the effect of Losartan ointment on hypertrophic scars and keloid, a total of

37 adult volunteers were randomly assigned into losartan 5 % or placebo treatment

groups. The treatment was performed twice-daily for 3 months and a 6-month follow-

up. The treatment was evaluated using Vancouver scar scale (VSS) method. A

total of 30 participants were analyzed (Losartan ointment n = 20; placebo ointment n

= 10; 7 placebo volunteers left the study because they thought the treatment was not

effective for them). In the Losartan group, VSS scores dropped significantly

(p < 0.01) both in keloid and hypertrophic scar patients.

Vascularity and pliability were significantly reduced by Losartan treatment

(p <0.05). The authors concluded that Losartan ointment (5 %) could alleviate

hypertrophic scars and keloids. These preliminary findings need to be validated by

well-designed studies.

Topical Oxandrolone for the Treatment of Hypertrophic Scars and Keloids

Sobec and colleagues (2019) noted that wound healing is a complex process.

Despite extensive studies, hypertrophic scars and keloids still occur, and could be

functionally and cosmetically problematic. In an attempt to prevent hypertrophic

scar formation, the effects of topical oxandrolone, using hyaluronic acid as a

biomaterial, were studied on ear wounds in rabbits. Deep 2nd-degree burns were

inflicted on each ear in 10 New Zealand rabbits. On the left ears, considered the

control side, hyaluronic acid gel was applied, whereas on the right ears, the study

side, a combination of oxandrolone and hyaluronic acid was applied. Dressings

were changed every 2 days for 2 weeks. At week 10, biopsy specimens from the

post-burn scars were harvested for histologic and immuno-histochemical

examinations. A total of 14 wounds were studied, 50 % on the control side and 50

% on the study side; 6 hypertrophic scars were encountered on the control side and

only 1 scar was encountered on the study side. In addition, an increased degree of

inflammation, an increased amount of collagen and fibroblast cellularity, increased

vascularization, and increased myofibroblast activity were observed on the control

side. The authors concluded that topical administration of oxandrolone using

hyaluronic acid as a biomaterial led to better healing and prevented hypertrophic

scar formation. These preliminary findings need to be further investigated in human

clinical trials.



Page 38 of 50

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Code Code Description

CPT codes covered if selection criteria are met:

17110 Destruction (e.g., laser surgery, electrosurgery, cryosurgery,

chemosurgery, surgical curettement), of benign lesions other than skin

tags or cutaneous vascular proliferative lesions; up to 14 lesions

[covered for keloid scar documented to be painful, ulcerated, pruritic

causing a functional impairment (i.e. restricted movement)]

17111 15 or more lesions [keloid scars]

11900 Injection, intralesional; up to and including 7 lesions [corticosteroids]

11901 more than 7 lesions[corticosteroids]

CPT codes not covered for indications listed in the CPB:

Extracorporeal shock wave therapy, Growth hormone releasing peptide 6, Intense pulsed light, Intralesional fiber laser device - no specific code:

0479T Fractional ablative laser fenestration of burn and traumatic scars for

functional improvement; first 100 cm2 or part thereof, or 1% of body

surface area of infants and children

0480T Fractional ablative laser fenestration of burn and traumatic scars for

functional improvement; each additional 100 cm2, or each additional 1%

of body surface area of infants and children, or part thereof (List

separately in addition to code for primary procedure)

20926 Tissue grafts, other (eg, paratenon, fat, dermis)

38232 Bone marrow harvesting for transplantation; autologous

38240 - 38241 Hematopoietic progenitor cell (HPC) transplantation

99183 Physician or other qualified health care professional attendance and

supervision of hyperbaric oxygen therapy, per session

Other CPT codes related to the CPB:

11042 - 11047 Debridement; subcutaneous tissue, muscle/fascia, bone

15852 Dressing change (for other than burns) under anesthesia (other than

local)

HCPCS codes covered for indications listed in the CPB:

J0702 Injection, betamethasone acetate 3 mg and betamethasone sodium

phosphate 3mg



Code Code Description

J1020 Injection, methylprednisolone acetate, 20 mg



J1100 Injection, dexamethasone sodium phosphate, 1 mg

J1700 Injection, hydrocortisone acetate, up to 25 mg

J1710 Injection, hydrocortisone sodium phosphate, up to 50 mg

J1720 Injection, hydrocortisone sodium succinate, up to 100 mg

J2650 Injection, prednisolone acetate, up to 1 ml

J3300 Injection, triamcinolone acetonide, preservative free, 1 mg

J3301 Injection, triamcinolone acetonide, not otherwise specified, 10 mg

J3302 Injection, triamcinolone diacetate, per 5 mg

J3303 Injection, triamcinolone hexacetonide, per 5 mg

J7638 Dexamethasone, inhalation solution, compounded product, administered

through DME, unit dose form, per milligram

J9190 Fluorouracil, 500 mg

Page 39 of 50

HCPCS codes not covered for indications listed in the CPB:

Dermal substitutes, Losartan ointment, Topical oxandrolone - no specific code:

A6025 Gel sheet for dermal or epidermal application, (e.g., silicone, hydrogel,

other), each

C9257 Injection, bevacizumab, 0.25 mg

G0277 Hyperbaric oxygen under pressure, full body chamber, per 30 minute

interval

J0585 Injection, onabotulinumtoxinA, 1 unit [Botox]

J0586 Injection, abobotulinumtoxinA, 5 units [Dysport]

J1438 Injection, etanercept, 25 mg

J3470 Injection, hyaluronidase, up to 150 units

J3471 Injection, hyaluronidase, ovine, preservative free, per 1 USP unit (up to

999 USP units)

J3472 Injection, hyaluronidase, ovine, preservative free, per 1,000 USP units

J3473 Injection, hyaluronidase, recombinant, 1 USP unit



Page 40 of 50


J9035

J9040

J9212

J9213

J9214

J9215

J9280

Q5107

ICD-10 codes covered if selection criteria are met:

L91.0

The above policy is based on the following references:

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and treatment of hypertrophic scars. Arch Surg. 1991;126:499-504.

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5. Sawada Y, Yotsuyanagi T, Ara M, et al. Experiences using silicone gel tie-

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6. Sawada Y, Ara M, Yotsuyanagi T, et al. Treatment of dermal depth burn

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1990;16:347-352.

7. Gibbons M, Zuker R, Brown M, et al. Experience with silastic gel sheeting in

pediatric scarring. J Burn Care Rehabil. 1994;15(1):69-73.

8. Carney SA, Cason CG, Gowar JP, et al. Cica-Care gel sheeting in the

management of hypertrophic scarring. Burns. 1994;20(2):163-167.


Page 41 of 50

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18. de Oliveira GV, Nunes TA, Magna LA, et al. Silicone versus nonsilicone gel

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20. Wittenberg GP, Fabian BG, Bogomilsky JL, et al. Prospective, single-blind,

randomized, controlled study to assess the efficacy of the 585-nm

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21. O'Brien L, Pandit A. Silicon gel sheeting for preventing and treating

hypertrophic and keloid scars. Cochrane Database Syst Rev. 2006;

(1):CD003826.



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Silicone gel sheet versus Kenalog injection treatment. Plast Reconstr Surg.

1992;90(6):988-992.

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27. Shaffer JJ, Taylor SC, Cook-Bolden F. Keloidal scars: A review with a critical

look at therapeutic options. J Am Acad Dermatol. 2002;46(2):S63-S97.

28. Porter JP. Treatment of the keloid. What's new? Otolaryngol Clin North Am.

2002;35(1):207-220, viii.

29. Brown CA. The use of silicon gel for treating children's burn scars in Saudi

Arabia: A case study. Occup Ther Int. 2002;9(2):121-30.

30. Eishi K, Bae SJ, Ogawa F, et al. Silicone gel sheets relieve pain and pruritus

with clinical improvement of keloid: Possible target of mast cells. J

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31. Food and Drug Administration. HHS. General and plastic surgery devices;

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32. Chan KY, Lau CL, Adeeb SM, et al. A randomized, placebo-controlled,

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33. Al-Attar A, Mess S, Thomassen JM, et al. Keloid pathogenesis and

treatment. Plast Reconstr Surg. 2006;117(1):286-300.

34. Meshkinpour A, Ghasri P, Pope K, et al. Treatment of hypertrophic scars

and keloids with a radiofrequency device: A study of collagen effects.

Lasers Surg Med. 2005;37(5):343-349.

35. Davison SP, Mess S, Kauffman LC, Al-Attar A. Ineffective treatment of

keloids with interferon alpha-2b. Plast Reconstr Surg. 2006;117(1):247-252.

36. al-Kawajah MM. Failure of interferon-alpha 2b in the treatment of mature

keloids. Int J Dermatol. 1996;35(7):515-517.



Page 43 of 50

37. Leventhal D, Furr M, Reiter D. Treatment of keloids and hypertrophic

scars: A meta-analysis and review of the literature. Arch Facial Plast Surg.

2006;8(6):362-368.

38. Asilian A, Darougheh A, Shariati F. New combination of triamcinolone,

5-fluorouracil, and pulsed-dye laser for treatment of keloid and

hypertrophic scars. Dermatol Surg. 2006;32(7):907-915.

39. Nanda S, Reddy BS. Intralesional 5-fluorouracil as a treatment modality of

keloids. Dermatol Surg. 2004;30(1):54-56.

40. Manuskiatti W, Fitzpatrick RE. Treatment response of keloidal and

hypertrophic sternotomy scars: Comparison among intralesional

corticosteroid, 5-fluorouracil, and 585-nm flashlamp-pumped pulsed-dye

laser treatments. Arch Dermatol. 2002;138(9):1149-1155.

41. Berman B, Perez OA, Konda S, et al. A review of the biologic effects, clinical

efficacy, and safety of silicone elastomer sheeting for hypertrophic and

keloid scar treatment and management. Dermatol Surg. 2007;33(11):1291

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42. Karrer S. Therapy of keloids. Hautarzt. 2007;58(11):979-989.

43. Sharma S, Bhanot A, Kaur A, Dewan SP. Role of liquid nitrogen alone

compared with combination of liquid nitrogen and intralesional

triamcinolone acetonide in treatment of small keloids. J Cosmet Dermatol.

2007;6(4):258-261.

44. Durani P, Bayat A. Levels of evidence for the treatment of keloid disease. J

Plast Reconstr Aesthet Surg. 2008;61(1):4-17.

45. Lacarrubba F, Patania L, Perrotta R, et al. An open-label pilot study to

evaluate the efficacy and tolerability of a silicone gel in the treatment of

hypertrophic scars using clinical and ultrasound assessments. J

Dermatolog Treat. 2008;19(1):50-53.

46. Durani P, Bayat A. Levels of evidence for the treatment of keloid disease. J

Plast Reconstr Aesthet Surg. 2008;61(1):4-17.

47. Berman B, Patel JK, Perez OA, et al. Evaluating the tolerability and efficacy

of etanercept compared to triamcinolone acetonide for the intralesional

treatment of keloids. J Drugs Dermatol. 2008;7(8):757-761.

48. Anzarut A, Olson J, Singh P, et al. The effectiveness of pressure garment

therapy for the prevention of abnormal scarring after burn injury: A meta-

analysis. J Plast Reconstr Aesthet Surg. 2009;62(1):77-84.



Page 44 of 50

49. Xiao Z, Zhang F, Cui Z. Treatment of hypertrophic scars with intralesional

botulinum toxin type A injections: A preliminary report. Aesthetic Plast

Surg. 2009;33(3):409-412.

50. van der Veer WM, Jacobs XE, Waardenburg IE, et al. Topical calcipotriol for

preventive treatment of hypertrophic scars: A randomized, double-blind,

placebo-controlled trial. Arch Dermatol. 2009;145(11):1269-1275.

51. Ceović R, Lipozenčić J, Bukvić Mokos Z, et al. Why don't we have more

effective treatment for keloids? Acta Dermatovenerol Croat. 2010;18

(3):195-200.

52. Shridharani SM, Magarakis M, Manson PN, et al. The emerging role of

antineoplastic agents in the treatment of keloids and hypertrophic scars: A

review. Ann Plast Surg. 2010;64(3):355-361.

53. Stoffels I, Wolter TP, Sailer AM, Pallua N. The impact of silicone spray on

scar formation. A single-center placebo-controlled double-blind trial.

Hautarzt. 2010;61(4):332-338.

54. Berman B. Biological agents for controlling excessive scarring. Am J Clin

Dermatol. 2010;11 Suppl 1:31-34.

55. Stavrou D, Weissman O, Winkler E, et al. Silicone-based scar therapy: A

review of the literature. Aesthetic Plast Surg. 2010;34(5):646-651.

56. Tosa M, Murakami M, Hyakusoku H. Effect of lidocaine tape on pain during

intralesional injection of triamcinolone acetonide for the treatment of

keloid. J Nihon Med Sch. 2009;76(1):9-12.

57. Lutgendorf MA, Adriano EM, Taylor BJ. Prevention and management of

keloid scars. Obstet Gynecol. 2011;118(2 Pt 1):351-356.

58. Pai VB, Cummings I. Are there any good treatments for keloid scarring

after sternotomy? Interact Cardiovasc Thorac Surg. 2011;13(4):415-418.

59. Goldstein BG, Goldstein AO. Keloids. UpToDate [online serial]. Waltham,

MA: UpToDate; reviewed February 2012.

60. Hayashida K, Akita S. Quality of pediatric second-degree burn wound scars

following the application of basic fibroblast growth factor: Results of a

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61. Verhaeghe E, Ongenae K, Bostoen J, Lambert J. Nonablative fractional laser

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controlled trial. Dermatol Surg. 2013;39(3 Pt 1):426-434.



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62. Waibel JS, Wulkan AJ, Shumaker PR. Treatment of hypertrophic scars using

laser and laser assisted corticosteroid delivery. Lasers Surg Med. 2013;45

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63. Jin R, Huang X, Li H, et al. Laser therapy for prevention and treatment of

pathologic excessive scars. Plast Reconstr Surg. 2013;132(6):1747-1758.

64. O'Brien L, Jones DJ. Silicone gel sheeting for preventing and treating

hypertrophic and keloid scars. Cochrane Database Syst Rev.

2013;9:CD003826.

65. Malhotra AK, Gupta S, Khaitan BK, Sharma VK. Imiquimod 5% cream for

the prevention of recurrence after excision of presternal keloids.

Dermatology. 2007;215(1):63-65.

66. Berman B, Harrison-Balestra C, Perez OA, et al. Treatment of keloid scars

post-shave excision with imiquimod 5% cream: A prospective, double-

blind, placebo-controlled pilot study. J Drugs Dermatol. 2009;8(5):455-458.

67. Cacao FM, Tanaka V, Messina MC. Failure of imiquimod 5% cream to

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68. Viera MH, Vivas AC, Berman B. Update on keloid management: Clinical and

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69. Ledon JA, Savas J, Franca K, et al. Intralesional treatment for keloids and

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70. Gold MH, Berman B, Clementoni MT, et al. Updated international clinical

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71. Song C. Hypertrophic scars and keloids in surgery: Current concepts. Ann

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72. Wat H, Wu DC, Rao J, Goldman MP. Application of intense pulsed light in

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73. Dogra S, Yadav S, Sarangal R. Microneedling for acne scars in Asian skin

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74. Chandrashekar BS, Sriram R, Mysore R, et al. Evaluation of microneedling

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75. Goyal NN, Gold MH. A novel triple medicine combination injection for the

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76. Goldstein BG, Goldstein AO. Keloids and hypertrophic scars. UpToDate

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77. Gauglitz GG. Management of keloid and hypertrophic scars following burn

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79. Bleasdale B, Finnegan S, Murray K, et al. The use of silicone adhesives for

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81. Verhiel S, Piatkowski de Grzymala A, van der Hulst R. Mechanism of action,

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82. Wang R, Mao Y, Zhang Z, et al. Role of verapamil in preventing and treating

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83. Danielsen PL, Rea SM, Wood FM, et al. Verapamil is less effective than

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86. Kwak DH, Bae TH, Kim WS, Kim HK. Anti-vascular endothelial growth factor

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87. Silva VZ, Albacete A Neto, Horácio GS, et al. Evidences of autologous fat

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88. Ai JW, Liu JT, Pei SD, et al. The effectiveness of pressure therapy (15-25

mmHg) for hypertrophic burn scars: A systematic review and meta-

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89. Liu DQ, Li XJ, Weng XJ. Effect of BTXA on inhibiting hypertrophic scar

formation in a rabbit ear model. Aesthetic Plast Surg. 2017;41(3):721-728.

90. Kafka M, Collins V, Kamolz LP, et al. Evidence of invasive and noninvasive

treatment modalities for hypertrophic scars: A systematic review. Wound

Repair Regen. 2017;25(1):139-144.

91. Ren Y, Zhou X, Wei Z, et al. Efficacy and safety of triamcinolone acetonide

alone and in combination with 5-fluorouracil for treating hypertrophic

scars and keloids: A systematic review and meta-analysis. Int Wound J.

2017;14(3):480-487.

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93. Fan D, Xia Q, Wu S, et al. Mesenchymal stem cells in the treatment of

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94. Lee HJ, Jang YJ. Recent understandings of biology, prophylaxis and

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95. Zhao JC, Zhang BR, Shi K, et al. Lower energy radial shock wave therapy

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96. Cui HS, Hong AR, Kim JB, et al. Extracorporeal shock wave therapy alters

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97. Fernandez-Mayola M, Betancourt L, Molina-Kautzman A, et al. Growth

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98. Ren J, Liu S, Wan J, et al. Effect of hyperbaric oxygen on the process of

hypertrophic scar formation in rabbit ears. J Cosmet Dermatol. 2018;17

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99. Monstrey S, Middelkoop E, Vranckx JJ, et al. Updated scar management

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100. Sheridan RL, MacMillan K, Donelan M, et al. Tunable dye laser neovessel

ablation as an adjunct to the management of hypertrophic scarring in

burned children: Pilot trial to establish safety. J Burn Care Rehabil. 1997;18

(4):317-320.

101. Parrett BM, Donelan MB. Pulsed dye laser in burn scars: Current concepts

and future directions. Burns. 2010;36(4):443-449.

102. Hultman CS, Friedstat JS, Edkins RE, et al. Laser resurfacing and

remodeling of hypertrophic burn scars: The results of a large, prospective,

before-after cohort study, with long-term follow-up. Ann Surg. 2014;260

(3):519-529.

103. Blome-Eberwein S, Gogal C, Weiss MJ, et al. Prospective evaluation of

fractional CO2 laser treatment of mature burn scars. J Burn Care Res.

2016;37(6):379-387.

104. Tao J, Champlain A, Weddington C, et al. Treatment of burn scars in

Fitzpatrick phototype III patients with a combination of pulsed dye laser

and non-ablative fractional resurfacing 1550 nm erbium:glass/1927 nm

thulium laser devices. Scars Burn Heal. 2018;4:2059513118758510.

105. Zuccaro J, Muser I, Singh M, et al. Laser therapy for pediatric burn scars:

Focusing on a combined treatment approach. J Burn Care Res. 2018;39

(3):457-462.

106. Rodriguez-Menocal L, Davis SS1, Becerra S, et al. Assessment of ablative

fractional CO2 laser and Er:YAG laser to treat hypertrophic scars in a red

Duroc pig model. J Burn Care Res. 2018;39(6):954-962.

107. Ramaut L, Hoeksema H, Pirayesh A, et al. Microneedling: Where do we

stand now? A systematic review of the literature. J Plast Reconstr Aesthet

Surg. 2018;71(1):1-14.

108. Guida S, Farnetani F, Nisticò SP, et al. New trends in botulinum toxin use in

dermatology. Dermatol Pract Concept. 2018;8(4):277-282.

109. Hao R, Li Z, Chen X, Ye W. Efficacy and possible mechanisms of Botulinum

Toxin type A on hypertrophic scarring. J Cosmet Dermatol. 2018;17(3):340

346.

110. Hedayatyanfard K, Ziai SA, Niazi F, et al. Losartan ointment relieves

hypertrophic scars and keloid: A pilot study. Wound Repair Regen. 2018;26

(4):340-343.

111. Gauglitz GG, Williams FN. Overview of the management of the severely

burned patient. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed February 2019.



Page 49 of 50

112. Wiktor A, Richards D. Treatment of minor thermal burns. UpToDate

[online serial]. Waltham, MA: UpToDate; reviewed February 2019.

113. Li K, Nicoli F, Xi WJ, et al. The 1470 nm diode laser with an intralesional

fiber device: A proposed solution for the treatment of inflamed and

infected keloids. Burns Trauma. 2019;7:5.

114. Sobec RL, Fodor L, Bodog F. Topical oxandrolone reduces ear hypertrophic

scar formation in rabbits. Plast Reconstr Surg. 2019;143(2):481-487.

115. Gauglitz GG. Hypertrophic scarring and keloids following burn injuries.

UpToDate [online serial]. Waltham, MA: UpToDate; reviewed March 2019.



Page 50 of 50

Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in

private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible

for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to

change.

Copyright © 2001-2019 Aetna Inc.



AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0389 Hypertrophic

Scars and Keloids

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania revised 06/20/2019

http://www.aetnabetterhealth.com/pennsylvania

Prior Authorization Review Panel MCO Policy Submission A ......sheeting is used to reduce the volume and increase the elasticity of hypertrophic and keloid scars, as a dressing for

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