EBM Special Topic Laser Therapy for Prevention and Treatment of Pathologic Excessive Scars 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 experience 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 various laser therapies. The pooled response rate, pooled standardized mean difference of Vancouver Scar Scale scores, scar height, erythema, and pliability were reported. Results: Twenty-eight well-designed clinical trials with 919 patients were included 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 532nm 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 erythema, scar texture, degrees of symptom relief, recurrence rates, and adverse effects. (Plast. Reconstr. Surg. 132: 1747, 2013.)
H
ypertrophic scars and keloids are characterized 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 prevention of hypertrophic scars and keloids include 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. Copyright © 2013 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0b013e3182a97e43
silicone gel, compression therapy, corticosteroid injections, cryotherapy, laser, antitumor/immunosuppressive agents, and surgical resection.5 The regimens used for keloid and hypertrophic scar treatment are mainly dependent on the subjective experience of therapists based on the degree of injury and the patient’s individual requirements rather than direct evidence from evidencebased medicine.6–8 In addition, although clinical research has led to the application of many different 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 interest in any of the products, devices, or drugs mentioned in this article.
www.PRSJournal.com
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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 photothermolysis, whereas several types target vascular tissue specifically based on the concept of selective photothermolysis, such as pulsed-dye laser therapy.10 Traditional ablative lasers including carbon dioxide 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, 1540nm nonablative fractional laser generates microcolumns 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 hemoglobin, making it ideal for the treatment of vascular 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 hypertrophic 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 examining 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 Strategy A comprehensive systematic review of related articles was conducted in November of 2012 using databases including MEDLINE (1980 to November 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 Clinical Trials.gov, PubMed, CenterWatch Clinical Trials Listings Service, Current Controlled Trials, Grey Literature 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 articles, 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.
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Selection Criteria To avoid selection bias, two independent reviewers (R.J. and X.L.H) who were blinded to the journal, author, and study institution performed 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 published 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 therapeutic interventions. Assessment of Methodologic Quality and Heterogeneity Each article was appraised critically for study quality and assigned a corresponding level of evidence according to the American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies. In addition, the Cochrane Collaboration’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 Extraction Data were extracted by one reviewer (R.J.) and checked for accuracy by another reviewer (X.L.H.). A standard data form was used to capture the following information: (1) characteristics of the study; (2) study participants; (3) intervention (laser devices, wavelength, treatment protocols); (4) duration of follow-up; (5) outcomes; and (6) adverse effects. The response rate was considered to be a primary outcome. The quantitative 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 Methods Data were entered into RevMan (version 5.1; The Cochrane Collaboration, 2011), STATA
Volume 132, Number 6 • Pathologic Excessive Scars (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 individual 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 Vancouver Scar Scale score, scar erythema, scar height, and pliability, were calculated using standardized mean differences. Statistical significance was defined as a value of p < 0.05 or a 95 percent confidence interval. Regression analyses were performed to estimate the effect of background variables (i.e., patient age, scar age, fluence, number of treatments, total fluence of treatment, and publication 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 Assessment Several strategies were adopted to assess the validity of our approach. A clinical heterogeneity 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 versus controlled), year of publication (in decades), and study quality (different levels of evidence according to the American Society of Plastic Surgeons Evidence Rating Scale).
RESULTS Research Results Our search of publications yielded 829 potential articles. Of these articles, 632 were excluded after we reviewed the title and abstract, leaving 197 for retrieval. After reviewing full articles and reference lists, there were 28 clinical trials that met all
Fig. 1. Flow chart of the search and selection process.
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Kuo et al., 200433 Manuskiatti et al., 200135 Manuskiatti and Fitzpatrick, 200234 Nouri et al., 200336 Nouri et al., 200937 Omranifard and Rasti, 200738
HS HS Prevention Prevention K, HS HS HS Prevention
22 6 30 14 48 20 47 13 15
585-nm PDL
HS Prevention Prevention HS
Prevention Prevention HS HS HS HS Prevention
17 23 12 13 30 10 10 11 19 80 13 15 20 20
585-nm PDL 585-nm PDL 585-nm PDL
585-nm PDL 585/595-nm PDL 585-nm PDL 2940-nm erbium laser 1540 nm 1550 nm: 595-nm PDL 585-nm PDL 532-nm KTP laser
K HS HS
HS
320
10,600-nm carbon dioxide laser 1540-nm nonablative laser 10,600-nm carbon dioxide laser 595-nm PDL 585-nm PDL
HS
K, HS HS HS HS
Disease
22 33 16 20
No.
1064-nm Nd:YAG 585-nm PDL 585-nm PDL 10,600-nm carbon dioxide laser 585-nm PDL 585-nm PDL 532-nm Q-switch/PDL 810-nm diode laser 830-nm diode laser 532-nm LBO laser 1540 nm 585-nm PDL 595-nm PDL
Intervention
49 ± 19.39 44.1 (20–67)
57.45 ± 9.27 NA
55 (38–67) 68 (48–85) 27.2 ± 4.8
32 (12–60) 53 ± 19 25–74
38.42 ± 12.28 18.9 (1–68)
37 (32.5–47) 44.3 (28–59)
NA
NA
41.4 47.0 ± 7.51 34 (8–67) 38 ± 16 42 (23–60) 59 ± 13.45
3.2 (1.8–3.8) (15–56 )
34.9 ± 15.6 NA 49 37 (16–55)
Age (yr) (range)
32 ± 54 0.5
>6 NA
0.5 0.5 8.9 ± 2.6
17 >6 7 (6–11.5)
0.3 11.8 ± 4.9
5 (2–13) 0.6
NA
27.5
0.3 0 9 (3–3) NA 1 0.5
18.5 (4–72) 21 ± 20.42
NA NA 17 36
Scar Age (mo)
S S
S S
S S S, T
NA S S
S S, B, T
B S
B
S, B
S S NA T S, B S
S S
S, B, T, B NA NA
Cause
II–V IV–V
I–III NA
I–IV I–III III
NA I–IV I–V
III–IV III–IV
II–IV III–V
NA
NA
I–IV NA II–IV II–IV NA I–IV
I–IV III–IV
NA NA I–III I–II
Skin Type
SGS, IC No
No No
NA No No
No PT, IC, antihistamines NA No No
NA No
Surgery, IC, 5-FU, carbon dioxide laser No
No NA NA No No NA
NA PT, SGS No IC, SGS, PT, and excision No IC
Treatment History
II I
II I
I I II
II I I
II II
I II
II
II
II II II I II I
I II
II I II I
Level of Evidence*
10 6
6 3
4 4 1
12 2 2
6 3
3 3
39
12
12 6 12 6 2 4
5 5
6 12 6 3
FU (mo)
Nd:YAG, neodymium:yttrium-aluminum-garnet; PDL, pulsed-dye laser; KTP, potassium-titanyl-phosphate; LBO, lithium triborate; NA, not available; HS, hypertrophic scars; K, keloids; B, burn; T, trauma, S, surgery; IC, intralesional corticosteroid; 5-FU, 5-fluorouracil; PT, pressure therapy; SGS, silicone gel sheeting; FU, follow-up duration. *Level of evidence was rated according to the American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies.
Wittenberg et al., 199941 Yun et al., 201142
Pham et al., 201139 Tierney et al., 200940
Kim et al., 201131 Kono et al., 200332
Ghalambor and Piplezadeh, 200628 Haedersdal et al., 200929 Jung et al., 201130
Capon et al., 201013 Carvalho et al., 201014 Cassuto et al., 201024 Cervelli et al., 201211 Chan et al., 200425 Conologue and Norwood, 200626 Dierickx et al., 199527
Alster, 200321 Bowes et al., 200212
Akaishi et al., 201219 Allison et al., 200320 Alster and Williams, 199523 Alster et al., 199822
Reference
Table 1. Characteristics of Included Studies
Plastic and Reconstructive Surgery • December 2013
Volume 132, Number 6 • Pathologic Excessive Scars of our criteria and were used for the meta-analysis. Figure 1 is a flow chart of our search results, numbers, and reasons for exclusion. Characteristics of Included Studies The 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 hypertrophic scars and three studies focused on treatment 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 interventions, 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 according to the American Society of Plastic Surgeons
Evidence Rating Scale for Therapeutic Studies was I to II. Validity Assessment A 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 publication bias. To test whether these biases could have affected the results, we repeated the analyses excluding part of the studies (e.g., published before the year 2000, uncontrolled studies, level II according to the American Society of Plastic Surgeons scale). These analyses produced similar summary estimates and did not affect the significance of either the primary or secondary outcomes. Primary Outcome The response rate from each study is the primary outcome of this meta-analysis. Specifically, 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 percent 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.
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Fig. 3. Meta-analysis for response rate using logit transformation. The black points represent the response rate reported by individual 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.
to treatment. Figure 3 shows a pooled estimate of the data. The gross response rate for laser therapy is 71 percent (95 percent CI, 63 to 78 percent), 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 prevention, hypertrophic scars, and keloids treatment, respectively. The odds ratios of different laser systems were analyzed in subgroups and are displayed in Figure 4.
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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 Outcomes Ten randomized controlled trials or welldesigned controlled clinical trials focused on hypertrophic scar management with comparable outcomes of scar height, Vancouver Scar Scales
Volume 132, Number 6 • Pathologic Excessive Scars
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 effective 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.
score, scar erythema (measured by spectrophotometer or laser Doppler imaging), and scar pliability were included in our meta-analysis for secondary outcomes. Table 2 shows a description for all of the included controlled clinical trials. 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 interrater 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 number of controlled clinical trials focusing on secondary 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
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Plastic and Reconstructive Surgery • December 2013 Table 2. Description of Included Controlled Trials for Secondary Outcomes Analysis Reference
Design
Alster and WIlliams, RCT (wp) 199523 CCT Carvalho et al., 201014 CCT (wp) Chan et al., 200425 Conologue and Norwood, 200626 Manuskiatti et al., 200135 Manuskiatti and Fitzpatrick, 200234 Nouri et al., 200336 Nouri et al., 200937 Wittenberg et al., 199941 Yun et al., 201142
Treatment Protocol*
Outcome Measurement
Risk of Bias
585-nm PDL
7.0 J/cm2, 450 μsec, 6–8 wk × 2
High
830-nm diode laser 585-nm PDL
10.4 J/cm2, 2 days × 4
Erythema, scar height, pliability, surface roughness VSS, pain, scar height
Intervention
RCT (wp) 595-nm PDL
8.0 J/cm2, 1.5 msec, 8 wk × 3–6 8.0 J/cm2, 1.5 msec, 4–8 wk × 3
Scar height, viscoelasticity, erythema VSS, VAS
RCT (wp) 585-nm PDL
3/5/7 J/cm2, 450 msec, 4 wk × 6 Scar height, erythema, pliability RCT (wp) 585-nm PDL 5 J/cm2, 4 wk × 6 Scar height, erythema, pliability RCT (wp) 585-nm PDL 3.5 J/cm2, 450 μsec, 4–10 wk × 3 VSS, VAS, histologic analysis VSS, VAS, histologic analysis RCT (wp) 585/595-nm PDL 3.5 J/cm2, 450 μsec, 4 wk × 3 RCT(wp) 585-nm PDL 6.5–8.0 J/cm2, 450 μsec, 8 wk × 4 Erythema, pliability, scar volume CCT 532-nm KTP 8 J/cm2, 25 msec, 2–3 wk × 2 VSS
High High Low Unclear Unclear Unclear Unclear High High
wp, within patients; PDL, pulsed-dye laser; KTP, potassium-titanyl-phosphate; VSS, Vancouver Scar Scale; VAS, visual analogue scale; SGS, silicone gel sheeting; RCT, randomized controlled trials; CCT, controlled clinical trials. *Treatment protocol including fluence, pulse duration, and treatment interval × number of treatments.
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 significant (p > 0.05). Figure 5 displays the results of the secondary outcomes of Vancouver Scar Scale score, scar height, pliability, and erythema accordingly. These results demonstrate that laser therapy is effective in improving overall scar appearance and reduces both scar height and degree of erythema of hypertrophic scars. Adverse Effects and Recurrence Twenty-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 erythema/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 without treatment. The gross complication rates reported range from 0 to 20 percent. The recurrence rate is an indispensable indicator of treatment efficacy assessment for hypertrophic scars and keloids, which is expected to be an important effect size of our meta-analysis. All of the included studies reported follow-up
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assessments of participants, with an average follow-up duration of 6.96 months (range, 1 to 39 months) (Table 1). However, none of these studies reported any recurrence or progression of responding scars during these follow-up visits. Regression Analyses and Subgroup Analyses Regression analyses were performed to estimate 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 significant 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 significant differences were observed between these subgroups (p = 0.29, p = 0.53, and p = 0.51, respectively).
DISCUSSION The primary pathologic feature of hypertrophic scar and keloids has been postulated to be
Volume 132, Number 6 • Pathologic Excessive Scars
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 interval 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.
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 initiates inflammation and in turn elevates vascular permeability, matrix metalloproteinase production, and collagen fiber fascicle decomposition.
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Fig. 6. Regression of treatment interval (above, left), skin type (above, right), and fluence (below) versus response rate. Blue dots represent 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 suggest 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).
Furthermore, tissue hypoxia caused by targeted vascular destruction leads to catabolism and decreased cellular function, thus preventing further 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 provided 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 prevention of abnormal scarring.44 These evidencebased medicine results suggest that we should reconsider the empiric use of the treatments for scar control more carefully. To date, this meta-analysis is
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the first to investigate the application of laser therapy for the prevention and treatment of hypertrophic 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 585/595nm pulsed-dye laser therapy proved to be better in
Volume 132, Number 6 • Pathologic Excessive Scars people with lighter skin color. As dark-skinned populations 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 remission. 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 difference 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, including 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 characterized 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 oxyhemoglobin absorption peak (542 nm), the clinical efficacy of this wavelength is justified theoretically by inducing the strongest photothermolysis. It is worth noting that although increasing numbers of randomized controlled trials have provided adequate evidence for us to confirm the efficacy 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 objective 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 recurrence 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 suggest 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.
CONCLUSIONS By conducting a thorough search of the literature 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 Hospital Shanghai Jiao Tong University School of Medicine 639 Zhizaoju Road Shanghai 200011, People’s Republic of China [email protected] [email protected]
REFERENCES 1. Ketchum LD, Cohen IK, Masters FW. Hypertrophic scars and keloids: A collective review. Plast Reconstr Surg. 1974;53:140–154. 2. English RS, Shenefelt PD. Keloids and hypertrophic scars. Dermatol Surg.1999;625:631–638. 3. Bayat A, McGrouther DA. Clinical management of skin scarring. Skinmed 2005;4:165–173. 4. Durani P, Bayat A. Levels of evidence for the treatment of keloid disease. J Plast Reconstr Aesthet Surg. 2008;61:4–17. 5. 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;8:362–368. 6. Sarrazy V, Billet, F, Micallef L, et al. Mechanisms of pathological scarring: Role of myofibroblasts and current developments. Wound Repair Regen. 2011;19:S10–S15. 7. Mustoe TA, Cooter RD, Gold MH, et al. International clinical recommendations on scar management. Plast Reconstr Surg. 2002;110:560–571. 8. Ogawa R. The most current algorithms for the treatment and prevention of hypertrophic scars and keloids. Plast Reconstr Surg. 2010;125:557–568. 9. Castro DJ, Abergel RP, Meeker C, et al. Effects of the Nd:YAG laser on DNA synthesis and collagen production in human skin fibroblast cultures. Ann Plast Surg. 1983;11:214–222. 10. Bourazi N, Davis SC. Nouri K. Laser treatment of keloids and hypertrophic scars. Dermatol Surg. 2007;46:80–88. 11. Cervelli V, Nicoli F, Spallone D, et al. Treatment of traumatic scars using fat grafts mixed with platelet-rich plasma, and resurfacing of skin with the 1540 nm nonablative laser. Clin Exp Dermatol. 2012;37:55–61. 12. Bowes LE, Nouri K, Berman B, et al. Treatment of pigmented hypertrophic scars with the 585 nm pulsed dye laser and the 532 nm frequency-doubled Nd:YAG laser in the Q-switched and variable pulse modes: A comparative study. Dermatol Surg. 2002;28:714–719. 13. Capon AC, Gossé AR, Iarmarcovai GN, et al. Scar prevention using Laser-Assisted Skin Healing (LASH) in plastic surgery. Aesthetic Plast Surg. 2010;34:438–436. 14. Carvalho RL, Alcântara PS, Kamamoto F,Cressoni MD, Casarotto RA. Effects of low-level laser therapy on pain and scar formation after inguinal herniation surgery: A
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Plastic and Reconstructive Surgery • December 2013 randomized controlled single-blind study. Photomed Laser Surg. 2010;28:417–422. 15. Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ.2011;343:d5928. 16. Baryza MJ, Baryza GA. The Vancouver Scar Scale: An administration tool and its interrater reliability. J Burn Care Rehabil. 1995;66:535–538. 17. Draaijers LJ, Tempelman FR, Botman YA, et al. The patient and observer scar assessment scale: A reliable and feasible tool for scar evaluation. Plast Reconstr Surg. 2004;113:1960–1967. 18. Egger M, Smith GD, Altman DG. Systematic Reviews in Health Care Meta-analysis in Context. 2nd ed. Kent: BMJ Publishing Group; 2001. 19. Akaishi S, Koike S, Dohi T, Kobe K, Hyakusoku H, Ogawa R. Nd:YAG laser treatment of keloids and hypertrophic scars. Eplasty 2012;12:e1. 20. Allison KP, Kiernan KN, Waters RA,Clement RM. Pulsed dye laser treatment of burn scars: Alleviation or irritation? Burns 2003;29: 207–213. 21. Alster T. Laser scar revision: Comparison study of 585-nm pulsed dye laser with and without intralesional corticosteroids. Dermatol Surg. 2003;29:25–29. 22. Alster TS, Lewis AB, Rosenbach A. Laser scar revision: Comparison of CO2 laser vaporization with and without simultaneous pulsed dye laser treatment. Dermatol Surg. 1998;24:1299–1302. 23. Alster TS, Williams CM. Treatment of keloid sternotomy scars with 585 nm flashlamp-pumped pulsed-dye laser. Lancet 1995;345:1198–1200. 24. Cassuto DA, Scrimali L, Siragò P. Treatment of hypertrophic scars and keloids with an LBO laser (532 nm) and silicone gel sheeting. J Cosmet Laser Ther. 2010;12:32–37. 25. Chan HH, Wong DS, Ho WS,Lam LK, Wei W. The use of pulsed dye laser for the prevention and treatment of hypertrophic scars in chinese persons. Dermatol Surg. 2004;30:987– 994; discussion 994. 26. Conologue TD, Norwood C. Treatment of surgical scars with the cryogen-cooled 595 nm pulsed dye laser starting on the day of suture removal. Dermatol Surg. 2006;32:13–20. 27. Dierickx C, Goldman MP, Fitzpatrick RE. Laser treatment of erythematous/hypertrophic and pigmented scars in 26 patients. Plast Reconstr Surg. 1995;95:84–92. 28. Ghalambor AA, Piplezadeh MH. Low level CO2 laser therapy in burn scars: Which patients benefit most? Pak J Med Sci. 2006;22:158–161. 29. Haedersdal M, Moreau KE, Beyer DM,Nymann P, Alsbjørn B. Fractional nonablative 1540 nm laser resurfacing for thermal burn scars: A randomized controlled trial. Lasers Surg Med. 2009;41:189–195. 30. Jung JY, Jeong JJ, Roh HJ, et al. Early postoperative treatment of thyroidectomy scars using a fractional carbon dioxide laser. Dermatol Surg. 2011;37:217–223. 31. Kim HS, Kim BJ, Lee JY, Kim HO, Park YM. Effect of the 595nm pulsed dye laser and ablative 2940-nm Er:YAG fractional
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laser on fresh surgical scars: An uncontrolled pilot study. J Cosmet Laser Ther. 2011;13:176–179. 32. Kono T, Erçöçen AR, Nakazawa H,Honda T, Hayashi N, Nozaki M. The flashlamp-pumped pulsed dye laser (585 nm) treatment of hypertrophic scars in Asians. Ann Plast Surg. 2003;51:366–371. 33. Kuo YR, Jeng SF, Wang FS, et al. Flashlamp pulsed dye laser (PDL) suppression of keloid proliferation through downregulation of TGF-beta1 expression and extracellular matrix expression. Lasers Surg Med. 2004;34:104–108. 34. Manuskiatti W, Fitzpatrick RE. Treatment response of keloidal and hypertrophic sternotomy scars: Comparison among intralesional corticosteroid, 5-fluorouracil, and 585nm flashlamp-pumped pulsed-dye laser treatments. Arch Dermatol. 2002;138:1149–1155. 35. Manuskiatti W, Fitzpatrick RE, Goldman MP. Energy density and numbers of treatment affect response of keloidal and hypertrophic sternotomy scars to the 585-nm flashlamppumped pulsed-dye laser. J Am Acad Dermatol. 2001;45:558–565. 36. Nouri K, Jimenez GP, Harrison-Balestra C,Elgart GW. 585nm pulsed dye laser in the treatment of surgical scars starting on the suture removal day. Dermatol Surg. 2003;29:65–73; discussion 73. 37. Nouri K, Rivas MP, Stevens M, et al. Comparison of the effectiveness of the pulsed dye laser 585 nm versus 595 nm in the treatment of new surgical scars. Lasers Med Sci. 2009;24:801–810. 38. Omranifard M, Rasti M. Comparing the effects of conventional method, pulse dye laser and erbium laser for the treatment of hypertrophic scars in Iranian patients. J Res Med Sci. 2007;12:277–281. 39. Pham AM, Greene RM, Woolery-Lloyd H,Kaufman J, Grunebaum LD. 1550-nm nonablative laser resurfacing for facial surgical scars. Arch Facial Plast Surg. 2011;13:203–210. 40. Tierney E, Mahmoud BH, Srivastava D, Ozog D,Kouba DJ. Treatment of surgical scars with nonablative fractional laser versus pulsed dye laser: A randomized controlled trial. Dermatol Surg. 2009;35:1172–1180. 41. Wittenberg GP, Fabian GF, Bogomilsky JL, et al. Prospective, single-blind, randomized, controlled study to assess the efficacy of the 585-nm flashlamp-pumped pulsed-dye laser and silicone gel sheeting in hypertrophic scar treatment. Arch Dermatol. 1999;135:1049–1055. 42. Yun JS, Choi JY, Kim WS, Lee GY. Prevention of thyroidectomy scars in Asian adults using a 532-nm potassium. Dermatol Surg. 2011;37:1747–1753. 43. Anzarut A, Olson J, Singh P, Rowe BH, Tredget EE. The effectiveness of pressure garment therapy for the prevention of abnormal scarring after burn injury: A meta-analysis. J Plast Reconstr Aesthet Surg. 2009;62:77–84. 44. O’Brien L, Pandit A. Silicon gel sheeting for preventing and treating hypertrophic and keloid scars. Cochrane Database Syst Rev. 2006;25(1):CD003826. 45. Amadeu T, Braune A, Mandarim-de-Lacerda C, Porto LC, Desmoulière A, Costa A. Vascularization pattern in hypertrophic scars and keloids: A stereological analysis. Pathol Res Pract. 2003;199:469–473.
Background: The management of hypertrophic scars and keloids remains a therapeutic challenge. Treatment regimens are currently based on clinical experience 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 various laser therapies. The pooled response rate, pooled standardized mean difference of Vancouver Scar Scale scores, scar height, erythema, and pliability were reported. Results: Twenty-eight well-designed clinical trials with 919 patients were included 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 532nm 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 erythema, scar texture, degrees of symptom relief, recurrence rates, and adverse effects. (Plast. Reconstr. Surg. 132: 1747, 2013.)
H
ypertrophic scars and keloids are characterized 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 prevention of hypertrophic scars and keloids include 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. Copyright © 2013 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0b013e3182a97e43
silicone gel, compression therapy, corticosteroid injections, cryotherapy, laser, antitumor/immunosuppressive agents, and surgical resection.5 The regimens used for keloid and hypertrophic scar treatment are mainly dependent on the subjective experience of therapists based on the degree of injury and the patient’s individual requirements rather than direct evidence from evidencebased medicine.6–8 In addition, although clinical research has led to the application of many different 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 interest in any of the products, devices, or drugs mentioned in this article.
www.PRSJournal.com
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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 photothermolysis, whereas several types target vascular tissue specifically based on the concept of selective photothermolysis, such as pulsed-dye laser therapy.10 Traditional ablative lasers including carbon dioxide 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, 1540nm nonablative fractional laser generates microcolumns 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 hemoglobin, making it ideal for the treatment of vascular 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 hypertrophic 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 examining 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 Strategy A comprehensive systematic review of related articles was conducted in November of 2012 using databases including MEDLINE (1980 to November 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 Clinical Trials.gov, PubMed, CenterWatch Clinical Trials Listings Service, Current Controlled Trials, Grey Literature 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 articles, 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.
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Selection Criteria To avoid selection bias, two independent reviewers (R.J. and X.L.H) who were blinded to the journal, author, and study institution performed 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 published 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 therapeutic interventions. Assessment of Methodologic Quality and Heterogeneity Each article was appraised critically for study quality and assigned a corresponding level of evidence according to the American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies. In addition, the Cochrane Collaboration’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 Extraction Data were extracted by one reviewer (R.J.) and checked for accuracy by another reviewer (X.L.H.). A standard data form was used to capture the following information: (1) characteristics of the study; (2) study participants; (3) intervention (laser devices, wavelength, treatment protocols); (4) duration of follow-up; (5) outcomes; and (6) adverse effects. The response rate was considered to be a primary outcome. The quantitative 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 Methods Data were entered into RevMan (version 5.1; The Cochrane Collaboration, 2011), STATA
Volume 132, Number 6 • Pathologic Excessive Scars (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 individual 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 Vancouver Scar Scale score, scar erythema, scar height, and pliability, were calculated using standardized mean differences. Statistical significance was defined as a value of p < 0.05 or a 95 percent confidence interval. Regression analyses were performed to estimate the effect of background variables (i.e., patient age, scar age, fluence, number of treatments, total fluence of treatment, and publication 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 Assessment Several strategies were adopted to assess the validity of our approach. A clinical heterogeneity 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 versus controlled), year of publication (in decades), and study quality (different levels of evidence according to the American Society of Plastic Surgeons Evidence Rating Scale).
RESULTS Research Results Our search of publications yielded 829 potential articles. Of these articles, 632 were excluded after we reviewed the title and abstract, leaving 197 for retrieval. After reviewing full articles and reference lists, there were 28 clinical trials that met all
Fig. 1. Flow chart of the search and selection process.
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Kuo et al., 200433 Manuskiatti et al., 200135 Manuskiatti and Fitzpatrick, 200234 Nouri et al., 200336 Nouri et al., 200937 Omranifard and Rasti, 200738
HS HS Prevention Prevention K, HS HS HS Prevention
22 6 30 14 48 20 47 13 15
585-nm PDL
HS Prevention Prevention HS
Prevention Prevention HS HS HS HS Prevention
17 23 12 13 30 10 10 11 19 80 13 15 20 20
585-nm PDL 585-nm PDL 585-nm PDL
585-nm PDL 585/595-nm PDL 585-nm PDL 2940-nm erbium laser 1540 nm 1550 nm: 595-nm PDL 585-nm PDL 532-nm KTP laser
K HS HS
HS
320
10,600-nm carbon dioxide laser 1540-nm nonablative laser 10,600-nm carbon dioxide laser 595-nm PDL 585-nm PDL
HS
K, HS HS HS HS
Disease
22 33 16 20
No.
1064-nm Nd:YAG 585-nm PDL 585-nm PDL 10,600-nm carbon dioxide laser 585-nm PDL 585-nm PDL 532-nm Q-switch/PDL 810-nm diode laser 830-nm diode laser 532-nm LBO laser 1540 nm 585-nm PDL 595-nm PDL
Intervention
49 ± 19.39 44.1 (20–67)
57.45 ± 9.27 NA
55 (38–67) 68 (48–85) 27.2 ± 4.8
32 (12–60) 53 ± 19 25–74
38.42 ± 12.28 18.9 (1–68)
37 (32.5–47) 44.3 (28–59)
NA
NA
41.4 47.0 ± 7.51 34 (8–67) 38 ± 16 42 (23–60) 59 ± 13.45
3.2 (1.8–3.8) (15–56 )
34.9 ± 15.6 NA 49 37 (16–55)
Age (yr) (range)
32 ± 54 0.5
>6 NA
0.5 0.5 8.9 ± 2.6
17 >6 7 (6–11.5)
0.3 11.8 ± 4.9
5 (2–13) 0.6
NA
27.5
0.3 0 9 (3–3) NA 1 0.5
18.5 (4–72) 21 ± 20.42
NA NA 17 36
Scar Age (mo)
S S
S S
S S S, T
NA S S
S S, B, T
B S
B
S, B
S S NA T S, B S
S S
S, B, T, B NA NA
Cause
II–V IV–V
I–III NA
I–IV I–III III
NA I–IV I–V
III–IV III–IV
II–IV III–V
NA
NA
I–IV NA II–IV II–IV NA I–IV
I–IV III–IV
NA NA I–III I–II
Skin Type
SGS, IC No
No No
NA No No
No PT, IC, antihistamines NA No No
NA No
Surgery, IC, 5-FU, carbon dioxide laser No
No NA NA No No NA
NA PT, SGS No IC, SGS, PT, and excision No IC
Treatment History
II I
II I
I I II
II I I
II II
I II
II
II
II II II I II I
I II
II I II I
Level of Evidence*
10 6
6 3
4 4 1
12 2 2
6 3
3 3
39
12
12 6 12 6 2 4
5 5
6 12 6 3
FU (mo)
Nd:YAG, neodymium:yttrium-aluminum-garnet; PDL, pulsed-dye laser; KTP, potassium-titanyl-phosphate; LBO, lithium triborate; NA, not available; HS, hypertrophic scars; K, keloids; B, burn; T, trauma, S, surgery; IC, intralesional corticosteroid; 5-FU, 5-fluorouracil; PT, pressure therapy; SGS, silicone gel sheeting; FU, follow-up duration. *Level of evidence was rated according to the American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies.
Wittenberg et al., 199941 Yun et al., 201142
Pham et al., 201139 Tierney et al., 200940
Kim et al., 201131 Kono et al., 200332
Ghalambor and Piplezadeh, 200628 Haedersdal et al., 200929 Jung et al., 201130
Capon et al., 201013 Carvalho et al., 201014 Cassuto et al., 201024 Cervelli et al., 201211 Chan et al., 200425 Conologue and Norwood, 200626 Dierickx et al., 199527
Alster, 200321 Bowes et al., 200212
Akaishi et al., 201219 Allison et al., 200320 Alster and Williams, 199523 Alster et al., 199822
Reference
Table 1. Characteristics of Included Studies
Plastic and Reconstructive Surgery • December 2013
Volume 132, Number 6 • Pathologic Excessive Scars of our criteria and were used for the meta-analysis. Figure 1 is a flow chart of our search results, numbers, and reasons for exclusion. Characteristics of Included Studies The 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 hypertrophic scars and three studies focused on treatment 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 interventions, 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 according to the American Society of Plastic Surgeons
Evidence Rating Scale for Therapeutic Studies was I to II. Validity Assessment A 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 publication bias. To test whether these biases could have affected the results, we repeated the analyses excluding part of the studies (e.g., published before the year 2000, uncontrolled studies, level II according to the American Society of Plastic Surgeons scale). These analyses produced similar summary estimates and did not affect the significance of either the primary or secondary outcomes. Primary Outcome The response rate from each study is the primary outcome of this meta-analysis. Specifically, 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 percent 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.
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Fig. 3. Meta-analysis for response rate using logit transformation. The black points represent the response rate reported by individual 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.
to treatment. Figure 3 shows a pooled estimate of the data. The gross response rate for laser therapy is 71 percent (95 percent CI, 63 to 78 percent), 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 prevention, hypertrophic scars, and keloids treatment, respectively. The odds ratios of different laser systems were analyzed in subgroups and are displayed in Figure 4.
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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 Outcomes Ten randomized controlled trials or welldesigned controlled clinical trials focused on hypertrophic scar management with comparable outcomes of scar height, Vancouver Scar Scales
Volume 132, Number 6 • Pathologic Excessive Scars
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 effective 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.
score, scar erythema (measured by spectrophotometer or laser Doppler imaging), and scar pliability were included in our meta-analysis for secondary outcomes. Table 2 shows a description for all of the included controlled clinical trials. 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 interrater 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 number of controlled clinical trials focusing on secondary 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
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Plastic and Reconstructive Surgery • December 2013 Table 2. Description of Included Controlled Trials for Secondary Outcomes Analysis Reference
Design
Alster and WIlliams, RCT (wp) 199523 CCT Carvalho et al., 201014 CCT (wp) Chan et al., 200425 Conologue and Norwood, 200626 Manuskiatti et al., 200135 Manuskiatti and Fitzpatrick, 200234 Nouri et al., 200336 Nouri et al., 200937 Wittenberg et al., 199941 Yun et al., 201142
Treatment Protocol*
Outcome Measurement
Risk of Bias
585-nm PDL
7.0 J/cm2, 450 μsec, 6–8 wk × 2
High
830-nm diode laser 585-nm PDL
10.4 J/cm2, 2 days × 4
Erythema, scar height, pliability, surface roughness VSS, pain, scar height
Intervention
RCT (wp) 595-nm PDL
8.0 J/cm2, 1.5 msec, 8 wk × 3–6 8.0 J/cm2, 1.5 msec, 4–8 wk × 3
Scar height, viscoelasticity, erythema VSS, VAS
RCT (wp) 585-nm PDL
3/5/7 J/cm2, 450 msec, 4 wk × 6 Scar height, erythema, pliability RCT (wp) 585-nm PDL 5 J/cm2, 4 wk × 6 Scar height, erythema, pliability RCT (wp) 585-nm PDL 3.5 J/cm2, 450 μsec, 4–10 wk × 3 VSS, VAS, histologic analysis VSS, VAS, histologic analysis RCT (wp) 585/595-nm PDL 3.5 J/cm2, 450 μsec, 4 wk × 3 RCT(wp) 585-nm PDL 6.5–8.0 J/cm2, 450 μsec, 8 wk × 4 Erythema, pliability, scar volume CCT 532-nm KTP 8 J/cm2, 25 msec, 2–3 wk × 2 VSS
High High Low Unclear Unclear Unclear Unclear High High
wp, within patients; PDL, pulsed-dye laser; KTP, potassium-titanyl-phosphate; VSS, Vancouver Scar Scale; VAS, visual analogue scale; SGS, silicone gel sheeting; RCT, randomized controlled trials; CCT, controlled clinical trials. *Treatment protocol including fluence, pulse duration, and treatment interval × number of treatments.
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 significant (p > 0.05). Figure 5 displays the results of the secondary outcomes of Vancouver Scar Scale score, scar height, pliability, and erythema accordingly. These results demonstrate that laser therapy is effective in improving overall scar appearance and reduces both scar height and degree of erythema of hypertrophic scars. Adverse Effects and Recurrence Twenty-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 erythema/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 without treatment. The gross complication rates reported range from 0 to 20 percent. The recurrence rate is an indispensable indicator of treatment efficacy assessment for hypertrophic scars and keloids, which is expected to be an important effect size of our meta-analysis. All of the included studies reported follow-up
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assessments of participants, with an average follow-up duration of 6.96 months (range, 1 to 39 months) (Table 1). However, none of these studies reported any recurrence or progression of responding scars during these follow-up visits. Regression Analyses and Subgroup Analyses Regression analyses were performed to estimate 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 significant 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 significant differences were observed between these subgroups (p = 0.29, p = 0.53, and p = 0.51, respectively).
DISCUSSION The primary pathologic feature of hypertrophic scar and keloids has been postulated to be
Volume 132, Number 6 • Pathologic Excessive Scars
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 interval 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.
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 initiates inflammation and in turn elevates vascular permeability, matrix metalloproteinase production, and collagen fiber fascicle decomposition.
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Fig. 6. Regression of treatment interval (above, left), skin type (above, right), and fluence (below) versus response rate. Blue dots represent 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 suggest 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).
Furthermore, tissue hypoxia caused by targeted vascular destruction leads to catabolism and decreased cellular function, thus preventing further 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 provided 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 prevention of abnormal scarring.44 These evidencebased medicine results suggest that we should reconsider the empiric use of the treatments for scar control more carefully. To date, this meta-analysis is
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the first to investigate the application of laser therapy for the prevention and treatment of hypertrophic 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 585/595nm pulsed-dye laser therapy proved to be better in
Volume 132, Number 6 • Pathologic Excessive Scars people with lighter skin color. As dark-skinned populations 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 remission. 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 difference 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, including 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 characterized 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 oxyhemoglobin absorption peak (542 nm), the clinical efficacy of this wavelength is justified theoretically by inducing the strongest photothermolysis. It is worth noting that although increasing numbers of randomized controlled trials have provided adequate evidence for us to confirm the efficacy 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 objective 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 recurrence 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 suggest 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.
CONCLUSIONS By conducting a thorough search of the literature 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 Hospital Shanghai Jiao Tong University School of Medicine 639 Zhizaoju Road Shanghai 200011, People’s Republic of China [email protected] [email protected]
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