laser therapy for prevention and treatment of.57
DESCRIPTION
jurnalTRANSCRIPT
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
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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
Plastic and Reconstructive Surgery • December 2013
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.
Volume 132, Number 6 • Pathologic Excessive Scars
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
Plastic and Reconstructive Surgery • December 2013
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.
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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
Plastic and Reconstructive Surgery • December 2013
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.
Volume 132, Number 6 • Pathologic Excessive Scars
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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).
Volume 132, Number 6 • Pathologic Excessive Scars
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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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