Laser Therapy for Prevention and Treatment of.57

www.PRSJournal.com 1747

Hypertrophic scars and keloids are charac-terized by pathologic changes of excessive deposition of collagen and glycoprotein.

These skin conditions affect millions of patients, with an incidence of 4 to 16 percent being observed among different populations.1–3 The abnormal scar formations lead to both cosmetic and functional problems; cause symptoms of pain, burning, and itching; and substantially affect quality of life.4,5

Current strategies for treatment and preven-tion of hypertrophic scars and keloids include

silicone gel, compression therapy, corticosteroid injections, cryotherapy, laser, antitumor/immu-nosuppressive agents, and surgical resection.5 The regimens used for keloid and hypertrophic scar treatment are mainly dependent on the subjec-tive experience of therapists based on the degree of injury and the patient’s individual require-ments rather than direct evidence from evidence-based medicine.6–8 In addition, although clinical research has led to the application of many dif-ferent types of therapies, there is no conclusion regarding which treatment is the best.1,3,7,8

Since the introduction of the neodymium: yttrium-aluminum-garnet laser in scar treatment in 1983 by Castro and colleagues,9 several laser systems have been shown to be effective in both

Disclosure: None of the authors has a financial in-terest in any of the products, devices, or drugs men-tioned in this article.Copyright © 2013 by the American Society of Plastic Surgeons

DOI: 10.1097/PRS.0b013e3182a97e43

Rui Jin, M.D.Xiaolu Huang, M.D.Hua Li, M.D., Ph.D.

Yuwen Yuan, M.D., Ph.D.Bin Li, M.D.

Chen Cheng, M.D.Qingfeng Li, M.D., Ph.D.

Shanghai, People's Republic of China

Background: The management of hypertrophic scars and keloids remains a therapeutic challenge. Treatment regimens are currently based on clinical ex-perience rather than substantiated evidence. Laser therapy is an emerging minimally invasive treatment that has recently gained attention.Methods: A meta-analysis was conducted to evaluate the effectiveness of vari-ous laser therapies. The pooled response rate, pooled standardized mean dif-ference of Vancouver Scar Scale scores, scar height, erythema, and pliability were reported.Results: Twenty-eight well-designed clinical trials with 919 patients were in-cluded in the meta-analysis. The overall response rate for laser therapy was 71 percent for scar prevention, 68 percent for hypertrophic scar treatment, and 72 percent 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.Conclusions: This study presents the first meta-analysis to confirm the efficacy and safety of laser therapy in hypertrophic scar management. The level of evidence for laser therapy as a keloid treatment is low. Further research is required to determine the mechanism of action for different laser systems and to examine the efficacy in quantifiable parameters, such as scar erythe-ma, scar texture, degrees of symptom relief, recurrence rates, and adverse effects. (Plast. Reconstr. Surg. 132: 1747, 2013.)

From the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Second Medical University.The first two authors contributed equally to this work as co–first authors.Received for publication February 20, 2013; accepted June 26, 2013.

Laser Therapy for Prevention and Treatment of Pathologic Excessive Scars

EBM SpEcial Topic

1748

Plastic and Reconstructive Surgery • December 2013

prevention and treatment of hypertrophic scars and keloids. Most of these lasers achieve their effect of scar remodeling through photothermol-ysis, whereas several types target vascular tissue specifically based on the concept of selective pho-tothermolysis, such as pulsed-dye laser therapy.10 Traditional ablative lasers including carbon diox-ide and erbium:yttrium-aluminum-garnet cause the deepest photothermal effect; however, a high recurrence rate of 39 to 92 percent limited further application.7 Compared with ablative lasers, 1540-nm nonablative fractional laser generates micro-columns of coagulated tissue that extend deep into the dermis, thus producing rapid and safer clinical results.11 Pulsed-dye laser relies on the concept of selective photothermolysis, whereby wavelengths are absorbed preferentially by hemo-globin, making it ideal for the treatment of vascu-lar tissues such as hypertrophic scars.8 Although the mechanism is still unclear, new laser systems including 810/830-nm and 532-nm lasers have also shown promising prospects, and have been proven effective, especially on pigmented hyper-trophic scars, and have relieved such symptoms as pain and pruritus.12–14

There is currently no meta-analysis assessing the efficacy and safety of existing laser therapies. Because both bench and bedside research has grown explosively in recent years, a meta-analysis examin-ing the efficacy of existing laser therapies will help clinical decision-making and direct future research in the field of hypertrophic scars and keloids.

MATERIALS AND METHODS

Search StrategyA comprehensive systematic review of related

articles was conducted in November of 2012 using databases including MEDLINE (1980 to Novem-ber of 2012), Embase (1988 to November of 2012), and the Cochrane Central Register of Controlled Trials (searched November of 2012). A search was performed of the gray literature, including Clini-cal Trials.gov, PubMed, CenterWatch Clinical Trials Listings Service, Current Controlled Trials, Grey Lit-erature Report, and Google Scholar. The key words used were a combination of the following: “cicatrix,” “hypertrophic,” “prevention,” “treatment,” “lasers,” “hypertrophic scar,” “keloid,” “nonablative laser,” and “ablative laser.” Reference lists of selected arti-cles, other related studies, and review articles were examined for eligible studies. The primary authors were contacted if published data were inadequate for conducting statistical analysis.

Selection CriteriaTo avoid selection bias, two independent

reviewers (R.J. and X.L.H) who were blinded to the journal, author, and study institution per-formed the search and screen of published works. Any disagreements between reviewers were resolved by consensus with another team member acting as an arbiter (Q.F.L.). To be eligible for inclusion, a study had to meet all of the following criteria: (1) clinical trials assessing laser therapy for the prevention or treatment of hypertrophic scars and keloids; (2) clear descriptions of wound causes (i.e., trauma, burn, or surgical procedure), wound sites, scar age, types of pretreatments; (3) monotherapy as an intervention; (4) articles pub-lished in English; and (5) inclusion of five or more cases. This systematic review focused on both scar prevention and treatment. Studies targeted to scars less than 1 month of age are considered preventive interventions, whereas those targeted to scars older than 1 month are considered thera-peutic interventions.

Assessment of Methodologic Quality and Heterogeneity

Each article was appraised critically for study quality and assigned a corresponding level of evi-dence according to the American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies. In addition, the Cochrane Collabora-tion’s tool for assessing risk of bias15 was used to assess risk of bias in controlled clinical trials. Two independent reviewers (R.J. and X.L.H) assessed each published study independently.

Data ExtractionData were extracted by one reviewer (R.J.)

and checked for accuracy by another reviewer (X.L.H.). A standard data form was used to cap-ture the following information: (1) characteristics of the study; (2) study participants; (3) interven-tion (laser devices, wavelength, treatment proto-cols); (4) duration of follow-up; (5) outcomes; and (6) adverse effects. The response rate was considered to be a primary outcome. The quan-titative measurements of scar height, variation of scores (e.g., Vancouver Scar Scale,16 Patient and Observer Scar Assessment Scale17), variation of color, and variation of skin texture were assessed as secondary outcomes of this meta-analysis.

Data Analysis and Statistical MethodsData were entered into RevMan (version

5.1; The Cochrane Collaboration, 2011), STATA

Volume 132, Number 6 • Pathologic Excessive Scars

1749

(version 10.1; StataCorp, College Station, Texas), and R software (version 2.15.0, package META; R Foundation, Vienna, Austria) for the primary and secondary outcomes. The response rates of indi-vidual studies were pooled and estimated using logit transformation. The odds ratios of each laser system were combined in subgroups using the Mantel-Haenszel method to compare the strength of therapeutic effect. Pooled estimates of effect sizes for secondary outcomes, including Vancou-ver Scar Scale score, scar erythema, scar height, and pliability, were calculated using standard-ized mean differences. Statistical significance was defined as a value of p < 0.05 or a 95 percent con-fidence interval.

Regression analyses were performed to esti-mate the effect of background variables (i.e., patient age, scar age, fluence, number of treat-ments, total fluence of treatment, and publica-tion year) to response rates. Subgroup analyses was performed to detect the possible sources of heterogeneity for participants of different scar histologic types, cause of wound, wound sites, skin types, and whether the scar was pretreated.

Validity AssessmentSeveral strategies were adopted to assess the

validity of our approach. A clinical heterogene-ity test (the I2 test) was used to test whether the underlying effect was the same across each of the studies. Values greater than 75 percent indicated a high level of heterogeneity.18 Funnel plot and the Begg test were used to detect publication bias. In addition, sensitivity analysis was performed to evaluate the stability of the pooled response rates according to study design (e.g., uncontrolled ver-sus controlled), year of publication (in decades), and study quality (different levels of evidence according to the American Society of Plastic Sur-geons Evidence Rating Scale).

RESULTS

Research ResultsOur search of publications yielded 829 poten-

tial articles. Of these articles, 632 were excluded after we reviewed the title and abstract, leaving 197 for retrieval. After reviewing full articles and refer-ence lists, there were 28 clinical trials that met all

Fig. 1. Flow chart of the search and selection process.

1750


Tabl

e 1.

Cha

ract

eris

tics

of I

nclu

ded

Stud

ies

Ref

eren

ce

Inte

rven

tion

No.

Dis

ease

Age

(yr

) (r

ange

)Sc

ar A

ge

(mo)

Cau

seSk

in

Typ

eT

reat

men

t H

isto

ryL

evel

of

Evi

denc

e*FU

(m

o)

Aka

ish

i et a

l., 2

01219

1064

-nm

Nd:

YAG

22K

, HS

34.9

± 1

5.6

NA

S, B

, T,

NA

NA

II6

Alli

son

et a

l., 2

00320

585-

nm

PD

L33

HS

NA

NA

BN

APT

, SG

SI

12A

lste

r an

d W

illia

ms,

199

52358

5-n

m P

DL

16H

S49

17N

AI–

III

No

II6

Als

ter

et a

l., 1

99822

10,6

00-n

m c

arbo

n d

ioxi

de

lase

r20

HS

37 (

16–5

5)36

NA

I–II

IC, S

GS,

PT,

an

d ex

cisi

onI

3

Als

ter,

2003

2158

5-n

m P

DL

22H

S3.

2 (1

.8–3

.8)

18.5

(4–

72)

SI–

IVN

oI

5B

owes

et a

l., 2

00212

585-

nm

PD

L53

2-n

m Q

-sw

itch

/PD

L6

HS

(15–

56 )

21 ±

20.

42S

III–

IVIC

II5

Cap

on e

t al.,

201

01381

0-n

m d

iode

lase

r30

Prev

enti

on41

.40.

3S

I–IV

No

II12

Car

valh

o et

al.,

201

01483

0-n

m d

iode

lase

r14

Prev

enti

on47

.0 ±

7.5

10

SN

AN

AII

6C

assu

to e

t al.,

201

02453

2-n

m L

BO

lase

r48

K, H

S34

(8–

67)

9 (3

–3)

NA

II–I

VN

AII

12C

erve

lli e

t al.,

201

21115

40 n

m20

HS

38 ±

16

NA

TII

–IV

No

I6

Ch

an e

t al.,

200

42558

5-n

m P

DL

47H

S42

(23

–60)

1S,

BN

AN

oII

2C

onol

ogue

an

d N

orw

ood,

20

0626

595-

nm

PD

L13

Prev

enti

on59

± 1

3.45

0.5

SI–

IVN

AI

4

Die

rick

x et

al.,

199

52758

5-n

m P

DL

15H

SN

A27

.5S,

BN

ASu

rger

y, I

C,

5-FU

, car

bon

di

oxid

e la

ser

II12

Gh

alam

bor

and

Pipl

ezad

eh,

2006

2810

,600

-nm

car

bon

dio

xide

la

ser

320

HS

NA

NA

BN

AN

oII

39

Hae

ders

dal e

t al.,

200

92915

40-n

m n

onab

lati

ve la

ser

17H

S37

(32

.5–4

7)5

(2–1

3)B

II–I

VN

AI

3Ju

ng

et a

l., 2

01130

10,6

00-n

m c

arbo

n d

ioxi

de

lase

r23

Prev

enti

on44

.3 (

28–5

9)0.

6S

III–

VN

oII

3

Kim

et a

l., 2

01131

595-

nm

PD

L12

Prev

enti

on38

.42

± 12

.28

0.3

SII

I–IV

No

II6

Kon

o et

al.,

200

33258

5-n

m P

DL

13H

S18

.9 (

1–68

)11

.8 ±

4.9

S, B

, TII

I–IV

PT, I

C,

anti

his

tam

ines

II3

Kuo

et a

l., 2

00433

585-

nm

PD

L30

K32

(12

–60)

17N

AN

AN

AII

12M

anus

kiat

ti e

t al.,

200

13558

5-n

m P

DL

10H

S53

± 1

9>6

SI–

IVN

oI

2M

anus

kiat

ti a

nd

Fitz

patr

ick,

20

0234

585-

nm

PD

L10

HS

25–7

47

(6–1

1.5)

SI–

VN

oI

2

Nou

ri e

t al.,

200

33658

5-n

m P

DL

11Pr

even

tion

55 (

38–6

7)0.

5S

I–IV

NA

I4

Nou

ri e

t al.,

200

93758

5/59

5-n

m P

DL

19Pr

even

tion

68 (

48–8

5)0.

5S

I–II

IN

oI

4O

mra

nif

ard

and

Ras

ti, 2

00738

585-

nm

PD

L29

40-n

m e

rbiu

m la

ser

80H

S27

.2 ±

4.8

8.9

± 2.

6S,

TII

IN

oII

1

Pham

et a

l., 2

01139

1540

nm

13H

S57

.45

± 9.

27>6

SI–

III

No

II6

Tie

rney

et a

l., 2

00940

1550

nm

:59

5-n

m P

DL

15H

SN

AN

AS

NA

No

I3

Wit

ten

berg

et a

l., 1

99941

585-

nm

PD

L20

HS

49 ±

19.

3932

± 5

4S

II–V

SGS,

IC

II10

Yun

et a

l., 2

01142

532-

nm

KT

P la

ser

20Pr

even

tion

44.1

(20

–67)

0.5

SIV

–VN

oI

6N

d:YA

G, n

eody

miu

m:y

ttri

um-a

lum

inum

-gar

net

; PD

L, p

ulse

d-dy

e la

ser;

KT

P, p

otas

sium

-tita

nyl

-ph

osph

ate;

LB

O, l

ith

ium

trib

orat

e; N

A, n

ot a

vaila

ble;

HS,

hyp

ertr

oph

ic sc

ars;

K, k

eloi

ds; B

, bur

n;

T, tr

aum

a, S

, sur

gery

; IC

, in

tral

esio

nal

cor

tico

ster

oid;

5-F

U, 5

-fluo

rour

acil;

PT,

pre

ssur

e th

erap

y; S

GS,

sili

con

e ge

l sh

eeti

ng;

FU

, fol

low

-up

dura

tion

.*L

evel

of e

vide

nce

was

rat

ed a

ccor

din

g to

the

Am

eric

an S

ocie

ty o

f Pla

stic

Sur

geon

s E

vide

nce

Rat

ing

Scal

e fo

r T

her

apeu

tic

Stud

ies.


1751

of our criteria and were used for the meta-analysis. Figure 1 is a flow chart of our search results, num-bers, and reasons for exclusion.

Characteristics of Included StudiesThe characteristics of selected studies are listed

in Table 1. There are 28 articles with 19 controlled trials and nine clinical trials published between 1995 and 2012 included in this review.11–15,19–42 Of these, 19 studies focused on treatment of hyper-trophic scars and three studies focused on treat-ment of keloids, including two studies focused on both diseases. The other eight studies focused on scar prevention, which included patients with postoperative linear scars. As for interven-tions, the majority of included studies focused on 585/595-nm pulsed-dye laser (n = 17), followed by 1540/1550-nm nonablative fractional laser (n = 4), 532-nm laser (n = 3), 10,600-nm carbon dioxide laser (n = 3), 810-nm/830-nm laser (n = 2), 2940-nm erbium laser (n = 1), and 1064-nm neodymium:yttrium-aluminum-garnet laser (n = 1), among which three trials compared two types of laser systems. In total, this systematic review involved 919 participants with 1129 scars. The age of participants ranged from 4 to 85 years. The level of evidence of included studies rated accord-ing to the American Society of Plastic Surgeons

Evidence Rating Scale for Therapeutic Studies was I to II.

Validity AssessmentA funnel plot (Fig. 2) showed that not all of

the studies were within the 95 percent confidence interval (the inverted funnel), which meant that the studies differed with respect to the size of the effect. The Begg test also revealed asymmetry (p = 0.00001), which indicated evidence of publi-cation bias. To test whether these biases could have affected the results, we repeated the analy-ses excluding part of the studies (e.g., published before the year 2000, uncontrolled studies, level II according to the American Society of Plastic Sur-geons scale). These analyses produced similar sum-mary estimates and did not affect the significance of either the primary or secondary outcomes.

Primary OutcomeThe response rate from each study is the

primary outcome of this meta-analysis. Specifi-cally, either an observer/patient-reported clinical improvement (e.g., reduction in scar thickness, better cosmetic outcome, relief of symptoms) or a more than 50 percent improvement in visual analogue scale score (e.g., Patient and Observer Scar Assessment Scale) was considered a response

Fig. 2. Funnel plot of response rate. Visual inspection of the funnel plot revealed asymmetry, which indicated evidence of publication bias. The pseudo–95 per-cent confidence interval is computed as part of the analysis that produces the funnel plot and corresponds to the expected 95 percent confidence interval for a given standard error. CO2, carbon dioxide; PDL, pulsed-dye laser.

1752


to treatment. Figure 3 shows a pooled estimate of the data. The gross response rate for laser ther-apy is 71 percent (95 percent CI, 63 to 78 per-cent), with rates of 68 percent (95 percent CI, 53 to 80 percent), 72 percent (95 percent CI, 62 to 80 percent), and 69 percent (95 percent CI, 29 to 92 percent) being observed for scar preven-tion, hypertrophic scars, and keloids treatment, respectively. The odds ratios of different laser systems were analyzed in subgroups and are dis-played in Figure 4.

According to this method, the 585/595-nm pulsed-dye laser and 532-nm laser systems proved to be the most effective laser systems. The odds ratios were 23.16 (95 percent CI, 9.23 to 58.06) and 28.42 (95 percent CI, 6.98 to 115.63), respectively.

Secondary OutcomesTen randomized controlled trials or well-

designed controlled clinical trials focused on hypertrophic scar management with comparable outcomes of scar height, Vancouver Scar Scales

Fig. 3. Meta-analysis for response rate using logit transformation. The black points represent the response rate reported by indi-vidual studies, the 95 percent confidence interval for each study is represented by a horizontal line, estimated total confidence interval is represented by a diamond on the bottom of the figure. Response rates of prevention studies and treatment studies are combined independently in subgroups. Heterogeneity is detected (i2 > 75 percent in the treatment subgroup), and a random effect model is used. W, weight; HS, hypertrophic scars.


1753

score, scar erythema (measured by spectropho-tometer or laser Doppler imaging), and scar pli-ability were included in our meta-analysis for secondary outcomes. Table 2 shows a descrip-tion for all of the included controlled clinical tri-als. Mean laser fluence is 6.6 J/cm2 (range, 3 to 10.4 J/cm2) received in four (range, two to six) sessions. The risk of bias of all included studies was assessed using the Cochrane Collaboration’s tool for assessing risk of bias with excellent inter-rater reliability (Cohen’s unweighted κ = 0.79).

The Vancouver Scar Scale score (0 to 13 points) change after laser therapy was −1.08 (95 percent CI, −1.45 to −0.72), and the 532 nm potassium-titanyl-phosphate laser therapy yielded the best result. Because of a relatively small num-ber of controlled clinical trials focusing on sec-ondary outcomes of scar height, erythema, and scar pliability, only the 585/595-nm pulsed-dye laser system for hypertrophic scar treatments was included in the meta-analysis. The decrease in scar height is presented in millimeters, whereas

Fig. 4. Meta-analysis of the clinical efficacy for different laser systems. The size of the rhombus represents weight according to the inverse of the variance in random effect model. odds ratios indicate the strength of effect for different subgroups. The most effec-tive therapy is the 532-nm laser system. n/N, number of patients improved or not improved/total number of patients; CO2, carbon dioxide; PDL, pulsed-dye laser.

1754


the improvements of erythema and scar pliability are presented in percentage of improvement. The results are statistically significant for scar height reduction and erythema improvement (p < 0.05). However, the results for scar pliability are not sig-nificant (p > 0.05). Figure 5 displays the results of the secondary outcomes of Vancouver Scar Scale score, scar height, pliability, and erythema accord-ingly. These results demonstrate that laser therapy is effective in improving overall scar appearance and reduces both scar height and degree of ery-thema of hypertrophic scars.

Adverse Effects and RecurrenceTwenty-three of 28 included studies were

presented with a statement in the results or discussion sections detailing adverse effects, in which seven trials reported that no adverse events occurred during treatment. Of the 16 trials reporting adverse events, transient ery-thema/purpura (n = 12), pain (n = 9), and edema (n = 7) were observed most often and were resolved in 7 to 10 days after treatment. More severe adverse events included crusting (n = 4), hyperpigmentation/hypopigmentation (n = 3), blister (n = 3), and superficial burn (n = 1), which resolved in 1 to 3 months with-out treatment. The gross complication rates reported range from 0 to 20 percent.

The recurrence rate is an indispensable indi-cator of treatment efficacy assessment for hyper-trophic scars and keloids, which is expected to be an important effect size of our meta-analysis. All of the included studies reported follow-up

assessments of participants, with an average fol-low-up duration of 6.96 months (range, 1 to 39 months) (Table 1). However, none of these stud-ies reported any recurrence or progression of responding scars during these follow-up visits.

Regression Analyses and Subgroup AnalysesRegression analyses were performed to esti-

mate the effect of background variables (i.e., patient age, scar age, skin types, energy density, and number of treatments) on the response rate of 585-nm pulsed-dye laser therapy using fractional polynomial regression. The results indicated that the response rate was influenced by the design of treatment protocols. The trend of the regression curves suggested that the response rate reached a peak when the treatment intervals were between 5 and 6 weeks (Fig. 6, above, left). In addition, the effect of laser therapy is better in patients with lighter skin types (Fig. 6, above, right). Conversely, the flat curve of regression analysis showed no sig-nificant correlation between energy density and response rate (Fig. 6, below).

Subgroup analyses were used to compare response rates between different wound sites, scar histologic types (keloids or hypertrophic scars), and pretreatment history (pretreated or not). No signif-icant differences were observed between these sub-groups (p = 0.29, p = 0.53, and p = 0.51, respectively).

DISCUSSIONThe primary pathologic feature of hypertro-

phic scar and keloids has been postulated to be

Table 2. Description of Included Controlled Trials for Secondary Outcomes Analysis

Reference Design InterventionTreatmentProtocol*

OutcomeMeasurement

Risk of Bias

Alster and WIlliams, 199523

RCT (wp) 585-nm PDL 7.0 J/cm2, 450 μsec, 6–8 wk × 2 Erythema, scar height, pliability, surface roughness

High

Carvalho et al., 201014

CCT 830-nm diode laser

10.4 J/cm2, 2 days × 4 VSS, pain, scar height High

Chan et al., 200425 CCT (wp) 585-nm PDL 8.0 J/cm2, 1.5 msec, 8 wk × 3–6 Scar height, viscoelasticity, erythema

High

Conologue and Norwood, 200626

RCT (wp) 595-nm PDL 8.0 J/cm2, 1.5 msec, 4–8 wk × 3 VSS, VAS Low

Manuskiatti et al., 200135

RCT (wp) 585-nm PDL 3/5/7 J/cm2, 450 msec, 4 wk × 6 Scar height, erythema, pliability

Unclear

Manuskiatti and Fitzpatrick, 200234

RCT (wp) 585-nm PDL 5 J/cm2, 4 wk × 6 Scar height, erythema, pliability

Unclear

Nouri et al., 200336 RCT (wp) 585-nm PDL 3.5 J/cm2, 450 μsec, 4–10 wk × 3 VSS, VAS, histologic analysis UnclearNouri et al., 200937 RCT (wp) 585/595-nm PDL 3.5 J/cm2, 450 μsec, 4 wk × 3 VSS, VAS, histologic analysis UnclearWittenberg et al.,

199941RCT(wp) 585-nm PDL 6.5–8.0 J/cm2, 450 μsec, 8 wk × 4 Erythema, pliability, scar

volumeHigh

Yun et al., 201142 CCT 532-nm KTP 8 J/cm2, 25 msec, 2–3 wk × 2 VSS Highwp, within patients; PDL, pulsed-dye laser; KTP, potassium-titanyl-phosphate; VSS, Vancouver Scar Scale; VAS, visual analogue scale; SGS, sili-cone gel sheeting; RCT, randomized controlled trials; CCT, controlled clinical trials.*Treatment protocol including fluence, pulse duration, and treatment interval × number of treatments.


1755

an imbalance of matrix degradation and collagen biosynthesis, resulting from excessive activation of fibroblasts and decreased collagen degradation. One of the most important effects of lasers in

treating scars is that they generate heat, which ini-tiates inflammation and in turn elevates vascular permeability, matrix metalloproteinase produc-tion, and collagen fiber fascicle decomposition.

Fig. 5. Meta-analyses for the secondary outcomes of Vancouver Scar Scale (VSS) scores, scar height, pliability, and erythema. The black points represent the effect size reported by an individual study in standard mean difference, the 95 percent confidence inter-val for each study is represented by a horizontal line, and the estimated total confidence interval is represented by a diamond on the bottom of the figure. The differences between laser treatment groups and control (no treatment) groups of all parameters are statistically significant (p < 0.05). PDL, pulsed-dye laser; IV, inverse of variance method; KTP, potassium-titanyl-phosphate.

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Furthermore, tissue hypoxia caused by targeted vascular destruction leads to catabolism and decreased cellular function, thus preventing fur-ther collagen deposition. Early application of laser to surgical incisions leads to a shorter acute inflammation phase, faster scar maturation, and increased tensile strength of the scar, which pro-vided the underlying mechanism for laser therapy as a prophylaxis for excessive scar formation.

A recent meta-analysis analyzing compression therapy for hypertrophic burn scar prevention showed no significant efficacy.43 Coincidentally, meta-analysis assessing silicone gel sheeting showed only weak evidence for a clinical benefit in the pre-vention of abnormal scarring.44 These evidence-based medicine results suggest that we should reconsider the empiric use of the treatments for scar control more carefully. To date, this meta-analysis is

the first to investigate the application of laser ther-apy for the prevention and treatment of hypertro-phic scars and keloids. Our study data suggest that laser therapy is efficacious and safe as a treatment for hypertrophic scars and prevention of excessive scar formation after surgery. However, based on existing data, the level of evidence for laser therapy as a keloid treatment is relatively not high enough to draw a robust conclusion in the present study. In addition, longer follow-up will be needed to prove the stability of its therapeutic effects.

In recent years, researchers have attempted to find the best treatment protocols for hypertrophic scars and keloids. Our meta-analysis has reached instructive conclusions through regression analyses and subgroup studies. The most meaningful result of our analyses is that the therapeutic effect of 585/595-nm pulsed-dye laser therapy proved to be better in

Fig. 6. Regression of treatment interval (above, left), skin type (above, right), and fluence (below) versus response rate. Blue dots rep-resent prediction points weighted by sample size. Red lines represent the predicted curve using the fractional polynomial method weighted by sample size. Gray lines represent the 95 percent confidence interval. Regression curves for treatment intervals sug-gest the response rate reaches a peak when the treatment intervals were between 5 and 6 weeks (above, left). The effect of laser therapy decreased when patient average skin type increased (above, right). a flat curve for energy density (fluence) suggests no correlation between energy density and response rate (below).


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people with lighter skin color. As dark-skinned popu-lations are more prone to complications caused by laser therapies, pulsed-dye laser on dark-skinned patients should be used cautiously. Our data also showed no significant correlation between the energy density and therapeutic effects. This result indicates that pulsed-dye laser therapy is not dose-related, and higher doses may cause irritation rather than remis-sion. As for treatment interval, our data suggested that the interval of 5 to 6 weeks yielded better results. Finally, our data analysis revealed no significant dif-ference in response rate between different scar ages and wound sites, which is consistent with the results of Alster and Chan et al.21,25

According to our data, 532-nm lasers, includ-ing 532-nm, frequency-doubled/Q-switched neodymium:yttrium-aluminum-garnet lasers, and 532-nm potassium-titanyl-phosphate lasers, were the most efficient of all laser systems.12,24,42 This finding can be explained by the mechanism of action of the laser on excessive scarring. Compared with normal skin, hypertrophic scars and keloids have a distinct vascularization pattern character-ized by a large amount of dilated vessels in both the papillary and the reticular dermis.45 Because 532 nm is the closest wavelength to the oxyhemo-globin absorption peak (542 nm), the clinical effi-cacy of this wavelength is justified theoretically by inducing the strongest photothermolysis.

It is worth noting that although increasing numbers of randomized controlled trials have pro-vided adequate evidence for us to confirm the effi-cacy of most of the laser therapies, the quality of these studies is still limited by inadequate sample sizes, short follow-up durations, and nonstandard results evaluations. Nevertheless, a lack of objec-tive and detailed reports of adverse effects is also a weak point for most of these studies. Another drawback is that existing research did not properly address the issue of recurrence after laser therapy, considering the generally accepted high recur-rence rate of these diseases. This may have been caused by the relatively short follow-up durations of most of the studies. It is also remarkable that validity assessment of our included studies showed significant publication bias; therefore, we sug-gest that randomized controlled trials with larger sample sizes, follow-up durations longer than 1 year, and detailed reports of adverse events will be required for further validation of our analysis.

CONCLUSIONSBy conducting a thorough search of the litera-

ture and applying strict inclusion and exclusion

criteria to primary studies, our analysis provides evidence that laser therapy is efficacious and safe for the prevention and treatment of hypertrophic scars. However, based on existing data, the level of evidence for laser therapy as a keloid treatment is still low. Although pulsed-dye laser and 532-nm laser systems yielded encouraging results, there is still a need for randomized controlled trials with high methodologic quality, larger sample sizes, and longer follow-up durations.

Qingfeng Li, M.D., Ph.D.Department of Plastic and Reconstructive Surgery

Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of Medicine

639 Zhizaoju RoadShanghai 200011, People’s Republic of China

[email protected]@yahoo.com

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