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New Combination of Triamcinolone, 5-Fluorouracil, and Pulsed-Dye Laser for Treatment of Keloid and Hypertrophic Scars ALI ASILIAN, MD, AFSHIN DAROUGHEH, MD,
AND
FAZLOLAH SHARIATI, MD
BACKGROUND Keloids and hypertrophic scars are benign growths of dermal collagen that usually cause major physical, psychological, and cosmetic problems. METHODS In this 12-week single-blinded clinical trial, 69 patients were randomly assigned into three study groups. In Group 1, intralesional triamcinolone acetonide (TAC, 10 mg/mL) was injected at weekly intervals for a total of 8 weeks. In Group 2 [TAC 1 5fluorouracil (5-FU)], 0.1 mL of 40 mg/mL TAC was added to 0.9 mL of 5-FU (50 mg/mL). This combination was injected weekly for 8 weeks. In Group 3, in addition to weekly TAC 1 5-FU injection for 8 weeks, lesions were irradiated by 585-nm flashlamp-pumped pulsed-dye laser (PDL, 5–7.5 J/cm 2) at the 1st, 4th, and 8th weeks. Lesions were assessed for erythema, pruritus, pliability, height, length, and width. RESULTS Sixty patients completed the study. At the 8- and 12-week follow-up visits, all groups showed an acceptable improvement in nearly all measures, but in comparison between groups, these were statistically more significant in the TAC 1 5-FU and TAC 1 5FU 1 PDL groups (po.05 for all). At the end of the study, the erythema score was significantly lower, and itch reduction was statistically higher in the TAC 1 5-FU 1 PDL group (po.05 for both). Good to excellent improvements (450% improvement) were reported by the patients as follows: 20% in Group 1, 55% in Group 2, and 75% in Group 3, all of which were significantly different (po.05). Good to excellent responses were reported by the blinded observer as follows: 15% in Group 1, 40% in Group 2, and 70% in Group 3. Their differences were statistically significant (po.05). Atrophy and telangiectasia were seen in 37% of patients in TAC group. CONCLUSION Overall efficacy of TAC 1 5-FU was comparable with TAC 1 5-FU 1 PDL, but the TAC 1 5-FU 1 PDL combination was more acceptable by the patients and produced better results. Its effect on lightening of the lesion was promising. The TAC 1 5-FU 1 PDL combination seems to be the best approach for treatment of keloid and hypertrophic scars. Ali Asilian, MD, Afshin Darougheh, MD, and Fazlolah Shariati, MD, have indicated no significant interest with commercial supporters.
K
eloids and hypertrophic scars are benign hyperproliferative growths of dermal collagen.1 Patients with these skin problems often experience major physical (deformities, restricted range of motion, pain, and pruritus) and psychological (cosmetic concern) problems.2
Although the basis for keloid and hypertrophic scar formation has not been fully delineated, it has been postulated that keloid- and hypertrophic scar–derived fibroblasts produce increased amounts of collagen per cell compared with normal fibroblasts.3 Thus, suppression of the overwhelming and uncontrolled fibroblast activity in
keloid and hypertrophic scar may be essential in therapeutic approaches to these abnormal wound responses.4 Increased vascularity has also occurred in keloid and hypertrophic scars.2,5 Transforming growth factor-b (TGF-b) has been implicated in the pathogenesis of the keloids.6,7
All authors are affilated with the Department of Dermatology, Isfahan University of Medical Sciences,
Isfahan, Iran & 2006 by the American Society for Dermatologic Surgery, Inc. Published by Blackwell Publishing ISSN: 1076-0512 Dermatol Surg 2006;32:907–915 DOI: 10.1111/j.1524-4725.2006.32195.x 907
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It is probably the combination of the proliferative scar fibroblasts’ abnormal response to TGF-b stimulation and elevated levels of this cytokine that is more important for keloid formation.8 There is no universally accepted treatment resulting in permanent hypertrophic or keloid scar ablation. Multiple modalities of treatment have been advocated. Most of these modalities have a variable and transient success. One of the long-term standards of keloid therapy, and the most commonly used therapeutic modality, is intralesional steroid injection. The corticosteroid inhibits a2-macroglobulin, which, in turn, inhibits collagenase. Once this pathway is blocked, collagenase is elaborated, thus enabling collagen degeneration.1 5-Fluorouracil (5-FU), a pyrimidine analog with antimetabolite activity, has been shown in tissue culture to inhibit fibroblast proliferation.9,10 It also has an inhibitory effect on TGF-b– induced type I collagen gene expression in human fibroblasts.11 The effect of flashlamp pulsed-dye laser (PDL) through selective damage of the microvasculature of the scar4 and down-regulation of TGF-b expression is also well known.12,13 With regard to these, in the present study the clinical response of keloid and hypertrophic scars is compared to treatment with intralesional triamcinolone acetonide (TAC) alone, TAC combined with 5-FU (TAC 1 5-FU), or TAC combined
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with 5-FU and 585-nm flashlamppumped PDL (TAC 1 5-FU 1 PDL).
Patients and Methods Study Design This is a 12-week, single-blinded, parallel-group, randomized clinical trial. The study protocol conformed to the guidelines of the 1975 Declaration of Helsinki and was approved by the review boards of dermatology department of St-Zahra Hospital (Isfahan, Iran) and Research Administration of Isfahan University of Medical Sciences. A total of 69 patients aged 5 to 70 years, who referred to Spadana Center of Dermatologic Consultation & Laser Therapy (Isfahan, Iran) were enrolled in this study. Informed consent was obtained from all subjects. All patients had complete blood cell counts along with renal and liver function tests checked before treatment as a baseline and at the end of the study. Patients who had previously been treated within the past 6 months, pregnant patients or patients planning pregnancy in the near future, lactating women, patients with chronic renal failure, or those showing any abnormalities of liver function tests or blood cell counts were excluded from the study. The lesions had to be a minimum of 10 mm in length. Only one lesion (preferably on the trunk or proximal extremities) per patient
was treated. They were randomly assigned in three study groups. In Group 1 (TAC), all patients were treated once weekly with intralesional TAC (10 mg/mL) for a total of eight sessions. In Group 2 (TAC 1 5-FU), 0.1 mL of 40 mg/ mL TAC was added to 0.9 mL of 5-FU (50 mg/mL). This combination was injected weekly for 8 weeks. In Group 3 (TAC 1 5-FU 1 PDL), in addition to eight weekly intralesional injections that were similar to Group 2, all patients were irradiated by a 585-nm PDL (Nlite System, EUPhotonics, Swansea, Wales, UK) with a pulse duration of 250 microseconds, at an energy density of 5 to 7.5 J/cm2 with a 5-mm spot and a single pass of spots overlapping 10% to 20% without cooling for three sessions at 1st, 4th, and 8th weeks. The solutions were injected into the body of the keloid using a 30gauge needle until slight blanching was clinically visible. The maximum volume of injection per square centimeter should not exceed 0.5 mL. The delivered dose was adjusted according to the extent of the lesions but did not exceed 2 mL per session. Only the firm portion of the keloid was treated by multiple injections, separated by approximately 1 cm. Assessments were carried out on the basis of patient satisfaction, observations, and measurements of a blinded observer (a derma-
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tology resident) and photographic records at the beginning and the 4th, 8th, and 12th weeks. At each assessment, the observer compared the photographs and measured the length, width, height, erythema, and pliability of the lesions. The observer also interviewed the patients and asked them about the symptoms and any adverse events encountered during the study. Evaluation Procedures Length, Width, and Height Scars were marked on every patient and mapped with a translucent paper at the first appointment to ensure the consistency of location. A dial caliper was used to determine greatest length, width, and height of the lesion (millimeter). Percentage of flattening was defined as the percentage of height reduction after treatment compared with baseline height (decrease in height/baseline height). Similar percentages were also defined for reduction in length and width. Erythema Erythema was graded by the observer on a 5-point scale as follows: 0 = no erythema; 1 = mild erythema; 2 = moderate erythema; 3 = severe erythema; and 4 = very severe erythema. Percentage of lesion lightening was defined as the percentage of erythema reduction compared with baseline erythema. Pliability Pliability was graded by the observer on a 5-point scale as follows: 0 = no induration; 1 = mild induration; 2 = moderate
induration; 3 = severe induration; and 4 = very severe induration. Percentage of lesion softening was defined as the percentage of pliability reduction compared with baseline pliability. Pruritus Severity of pruritus was graded by the patient on a 5-point scale as follows: 0 = no pruritus; 1 = mild pruritus; 2 = moderate pruritus; 3 = severe pruritus; and 4 = very severe pruritus. Percentage of itch reduction was defined as the percentage of pruritus reduction compared with baseline pruritus. Patient Self-Assessment At the 4th, 8th, and 12th weeks of the study, overall improvement was subjectively graded by patients on a 5-point scale as follows: no improvement; poor = up to 25% improvement; fair = 26% to 50% improvement; good = 51% to 75% improvement; and excellent = 76% to 100% improvement. Observer Assessment At the 4th, 8th, and 12th weeks of the study, overall improvement was graded by the observer by comparison of standardized photographs taken at 4-week intervals. Improvement scale was similar to patient selfassessment scale. Statistical Analysis Statistical analysis was carried out with computer software (SPSS 11.5 software for Windows, SPSS Inc., Chicago, IL, USA). Standard twotailed, paired t test analyses were performed within each study
group to compare means of each follow-up visit with the baseline. One-way analysis of variance, post hoc, and chi-square tests were performed to compare between three study groups at baseline, 4th, 8th, and 12th weeks. All statistical tests were two-tailed with a significance level of .05 (p o.05).
Results Baseline Characteristics Sixty of 69 patients who were enrolled into the study completed the full 12-week follow-up period. Sixty percent of the patients were female. Mean ages of the patients and mean duration of the lesions were 24.7 years (SD, 11.0 years) and 33.9 months (SD, 34.8 months), respectively. The site distribution was as follows: 38.5% on the face and neck, 35% on the trunk, 21.7% on proximal extremities, and 5% on distal extremities. At baseline, there were no statistically significant differences in means of age, duration, length, width, height, erythema, pruritus, and pliability between all study groups (Table 1).
Length, Width, and Height In comparison with the baseline, there was a statistically significant decrease in length, width, and height in all three study groups at the 4th, 8th, and 12th weeks (po .05 for all). There were only two
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TABLE 1. Demographic Features and Baseline Characteristics Group 1
Group 2
Group 3
Variable
(TAC)
(TAC 1 5-FU)
(TAC 1 5-FU 1 PDL)
p Valuey
Gender (male/female), No. (%) Age (years) Duration(months) Length (mm) Width (mm) Height (mm) Erythema score Pliability score Pruritus score
7/13 23.4 12.6 34.1 12.7 3.7 3.0 2.4 2.6
8/12 25.3 12.2 36.9 12.7 3.3 3.3 2.5 2.4
9/11 25.5 11.6 33.1 10.0 3.4 3.2 2.8 2.6
.812 .816 .910 .952 .633 .820 .574 .386 .838
(35/65) (8.0) (7.4) (26.7) (11.3) (1.9) (1.0) (1.0) (1.3)
(40/60) (11.9) (7.3) (50.27) (11.8) (1.6) (0.7) (1.0) (1.8)
(45/55) (13.0) (6.0) (37.6) (6.4) (2.8) (1.1) (0.8) (1.5)
Data are reported as mean 7 SD. y
All p values were greater than .05 (no statistically significant differences between groups were determined).
In comparison between three groups at the 4th and 12th weeks, percentage of length reduction in the TAC 1 5-FU and TAC 1 5-FU 1 PDL groups was statistically more than in TAC group (po.05 for both). Percentage of width reduction in the TAC 1 5-FU group at the 4th week was statistically more than both other groups (po.05 for both). In contrast, at the 8th and 12th weeks, higher percentages of width reduction were observed in both the TAC 1 5-FU and the TAC 1 5-FU 1 PDL groups, compared to the TAC group (pr.001 for both).
(po.05; Figure 1). Percentages of lesion flattening at the 4th, 8th, and 12th weeks were statistically higher in the TAC 1 5-FU and TAC 1 5-FU 1 PDL groups, compared with the TAC group (po .01 for all). At the end of the study, the average lesion flattened 50, 77, and 79% in Groups 1, 2, and 3, respectively. Erythema The decrease in erythema score was statistically significant in all
study groups during all follow-up visits (po.05 for all). In comparison between three study groups at the 8th week, the erythema score in the TAC group was significantly higher than the TAC 1 5-FU and TAC 1 5-FU 1 PDL groups (po.05 for both). At the end of the study, this measure in the TAC 1 5-FU 1 PDL group was significantly lower than the TAC and TAC 1 5-FU groups (po.05 for both) (Figure 2). Higher percentages of lesion
5 4.5 4
3.7
3.5
3.5 Height (mm)
exceptions; both of them were in the TAC group. The first was decrease in height at the 4th week, and the second was decrease in length at the 8th week.
3
3.4
3.3
3.2 2.6
baseline 4th week 8th week 12th week 2.8
2.5
2.5 1.8
1.7
2 1.5
1.2
1.2
1 0.5
Lower mean heights of lesions were observed at the 8th and 12th weeks in the TAC 1 5-FU and TAC 1 5-FU 1 PDL groups
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0 TAC
TAC+5-FU Group
TAC+5-FU+PDL
Figure 1. Mean lesion height reduction during 12-week follow-up.
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4 3.5
Erythema score
3
3.3 3 3 2.7
baseline 4th week 8th week 12th week
3.2 3
2.9
2.5 1.9
2
2
Observer Assessment
2 1.7
1.5
group (po.05). At the same visit, percentage of itch reduction in Group 3 was significantly greater than in the TAC group (po.05).
At the last visit, the highest and lowest improvements were observed in the TAC 1 5-FU 1 PDL and TAC groups, respectively (Figure 5). Their differences were statistically significant (po.05). At the same visit, good to excellent response observed as follows: 15% in the TAC group, 40% in the TAC 1 5-FU group, and 70% in the TAC 1 5-FU 1 PDL group, all of which were significantly different (po.05).
Patient Self-Assessment
Adverse Events
At the end of the study, patient self-assessment was highest in the TAC 1 5-FU 1 PDL group and lowest in the TAC group (Figures 3 and 4). Their differences were statistically significant (po.05). At the same visit, good to excellent improvement (improvement of 50% or higher) was reported by the patients as follows: 20% in the TAC group, 55% in the TAC 1 5-FU group, and 75% in
During the study, no abnormalities were detected in the laboratory data. Nearly all injections were painful. In the TAC group, 37% of patients reported some degree of skin atrophy and telangiectasia.
1.2
1 0.5 0 TAC
TAC+5-FU TAC+5-FU+PDL Group
Figure 2. Decrease in erythema score during 12-week follow-up.
lightening at the 8th and 12th weeks were found in both the TAC 1 5-FU and the TAC 1 5-FU 1 PDL groups, compared with the TAC group, both of which were statistically significant (po.05 for all). Pliability A statistically significant softening of lesions versus baseline was observed in all three study groups at the 8th and 12th weeks (po.05 for all). Improvement in pliability was also progressive. In comparison between groups, however, pliability scores and percentages of softening were not significantly different.
the TAC 1 5-FU 1 PDL group, all of which were significantly different (po.05).
In the TAC 1 5-FU 1 PDL group, the areas treated with the PDL became purpuric, which lasted from 7 to 10 days. On conclusion
Pruritus Severity of pruritus was significantly decreased versus baseline in all study groups at all follow-up visits (po.05 for all). At the 12th week, there was a statistically significant decrease in pruritus score in the TAC 1 5-FU 1 PDL group compared with the TAC
Figure 3. Burn scars of a patient in the TAC 1 5-FU 1 PDL group before and after treatment.
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100
not improved poor response fair response good response excellent response
90
% of patients
80 70
60 55
60
55
45
50 40 30
20
20
20
15
20
10
10 0 TAC
TAC+5-FU Group
TAC+5-FU+PDL
Figure 4. Patient self-assessment at the end of the study.
of the study, neither adverse textural nor pigmentary alterations were observed in either the TAC 1 5-FU or the TAC 1 5-FU 1 PDL group. Ulcers or erosions were also not seen.
Discussion The efficacy of corticosteroid injections in the treatment of keloids and hypertrophic scars has been well established. The most commonly used corticosteroid is TAC. The dosage and treatment interval have arbitrarily varied
from 10 to 40 mg/mL administered at intervals of 4 to 6 weeks for several months or until the scar is flattened. Although intralesional TAC administration has shown 50% to 100% clinical efficacy,14 the outcome has been uncertain and associated with multiple adverse effects, including atrophy, telangiectasia, and pigmentary changes, which are not acceptable adverse effects for most patients.15,16 In the present study, even though all indices in TAC group were improved, patient self-assessment and observer
100
not improved poor improvement fair improvement good improvement excellent improvement
90
% of patients
80 70
60
60
55
50
50 40
35
30
30
20 15
20 10
5
5
15
10
0 TAC
TAC+5-FU Group
TAC+5-FU+PDL
Figure 5. Observer assessment at the end of the study.
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assessment were only 20 and 15%, respectively. These relatively low improvements are probably related to relatively short follow-up duration (12 weeks). The rate of adverse reaction in this group was approximately equal to that in the study by Manuskiatti and colleagues,4 which was 40%. Fitzpatrick17 was the first who reported his 9-year experience administering more than 5,000 injections to more than 1,000 patients. He found that by mixing 1 mg/mL TAC with the 5-FU (by adding 0.1 mL of 10 mg/mL TAC to 0.9 mL of 50 mg/mL 5-FU), efficacy was improved and injections were less painful. Patients returned for injections a mean of 5 to 10 times. Fibroblast regression is dependent on the duration of exposure to the drug and the dose.18 It has been found that 5FU delivered intralesionally once weekly or once every 2 weeks in keloids and hypertrophic scars is effective.4,17,19 All the literature relating to the role of corticosteroids in keloid therapy suggests that a dose of 10 to 40 mg/mL TAC is required to be effective in keloid or hypertrophic scars.20 The mixture of corticosteroid used in TAC 1 5-FU combination would result in a concentration equivalent to 4 mg/ mL triamcinolone, which would not be expected to have any efficacy in treatment of patients. It was employed for its effect on potential 5-FU–induced inflammation.21
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The results of our study in the TAC 1 5-FU group are comparable to those reported previously.14,17 Nanda and Reddy14 reported that almost 80% of their patients showed more than 50% improvement. Again, lower improvement in our study is probably related to short follow-up period. In comparison with TAC group, it seems that TAC 1 5-FU combination is more effective and provides a more rapid response with few if not at all side effects. Our results are in line with that of Apikian and Goodman21 who found that intralesional 5-FU mixed with low-dose corticosteroid may be a possible alternative for the treatment of keloid scars and may have fewer undesirable side effects when compared with intralesional potent corticosteroids alone. Comparable results have been reported by other investigators.4,19,20 As Nanda and Reddy14 said, at the end of our study there were no serious systemic side effects in Groups 2 and 3. Systemic 5-FU can cause anemia, leukopenia, and thrombocytopenia. Even though 90 mg of 5-FU was not exceeded at each injection session, the use of higher doses has been reported without development of any adverse hematologic effects.17,19 The effectiveness of PDL in the treatment of keloids and hypertrophic scars is controversial. It
has been thought to be mediated by selective damage of the microvasculature of the scar.22 Dierickx and coworkers23 used a 585-nm PDL (6–7.5 J/cm2, 5-mm spot size) to treat hypertrophic scars, and after a mean number of 1.8 treatment sessions, the mean degree of improvement as judged by the treating physician was 77%.23 In some patients whose scars responded to TAC 1 5-FU injections, PDL was added by Fitzpatrick17 to eliminate residual erythema. Alster and Williams24 treated 16 patients with sternotomy scars by PDL and detected significant degrees of improvement in terms of color and skin thickness. A mean improvement in nonfacial scars of 81% after 2 1/2 treatments with PDL was reported by Goldman and Fitzpatrick.25 These positive results were confirmed by Manuskiatti and colleagues.2 In addition, they noted a significantly higher percentage of scar flattening after more than two treatments. In contrast, Wittenberg and associates,26 in the study of the efficacy of the 585-nm PDL in treatment of hypertrophic scars, showed that the clinical improvement in scar sections treated with four PDL irradiations at 8-week intervals was no different than that in control sections. More recently, another controlled study using PDL indicated that although patients’ pruritus improved, the reduction in terms of erythema or scar thickness was insignificant.27 These observations are consistent with data of Chan and colleagues5
that indicated that although most of the patients reported improvement, objective assessment did not indicate significant changes once the changes in the control sections were taken into consideration. Nouri and coworkers28 examined the role of PDL (10-mm spot size and a fluence of 3.5 J/cm2) in the treatment of surgical scars, and they suggested that scar location can have an effect on facial, shoulder, and arms scars, which respond better than those in the anterior chest walls. Reiken and associates22 reported a fluence-dependent inhibition of hypertrophic scar implants in mice that was proportional to the fluence from 6 to 10 J/cm2 using a candela PDL. In contrast, previous clinical studies on the PDL treatment of scars noted no significant difference in the treatment outcome versus minor variations in fluence used (6.0– 7.5 J/cm2).23,25 Similarly, Manuskiatti and associates2 noted no statistically significant fluence dependence of the clinical improvement of keloid and hypertrophic scars after PDL treatment. A trend toward better response with lower fluence was observed, however. A recent review article suggested that the fluence to be used for the treatment of hypertrophic scars should range from 4.5 to 7.5 J/ cm2, depending on the spot size (5–10 mm with higher fluence used for smaller spot size).5 Therefore, the authors treated our
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patients with 5 to 7.5 J/cm2 (5mm spot size) for three sessions and 70% to 75% of them showed more than 50% improvement. It seems that the difference in results can be due to several factors. Some of them are scar location and duration, different laser settings, skin types, follow-up duration, and subjective or objective assessments. Our follow-up period was only 12 weeks. As Manuskiatti and Fitzpatrick4 said, continuous improvement was sustained even 10 to 12 weeks after the end of their study. Perhaps multiple sequential laser treatments and longer follow-up may be essential for achieving a better clinical response. In comparison with TAC and TAC 1 5-FU groups, the TAC 1 5-FU 1 PDL combination is more effective and provides a more rapid response with few side effects. This results in a relatively short treatment period indicating that this combination may have a synergistic effect on keloid and hypertrophic scars. In conclusion, it must be said that it is the first randomized clinical trial that compares the TAC 1 5-FU 1 PDL combination with TAC alone or TAC 1 5-FU in treatment of keloid and hypertrophic scars. Both subjective and objective assessments were used to evaluate the efficacy of these modalities. Even though all treatment groups in our study showed an acceptable improvement in nearly
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all measures, these were more significant in the TAC 1 5-FU 1 PDL group. This combination was also more acceptable by the patients. Its effect on itch reduction and lightening of the lesion was promising. The TAC 1 5-FU 1 PDL combination seems to be the best approach for treatment of keloid and hypertrophic scars.
Acknowledgment We are very grateful to personnel of Spadana Center of Dermatologic Consultation & Laser Therapy for their help in our research.
References 1. Kelly AP. Medical and surgical therapies for keloids. Dermatol Ther 2004;17: 212–8. 2. Manuskiatti W, Fitzpatrick RE, Goldman MP. Energy density and numbers of treatment affect response of keloidal and hypertrophic sternotomy scars to the 585-nm flashlamp-pumped pulsed-dye laser. J Am Acad Dermatol 2001;45: 557–65. 3. Tuan T, Nichter LS. The molecular basis of keloid and hypertrophic scar formation. Mol Med Today 1998;4:19–24. 4. Manuskiatti W, Fitzpatrick RE. Treatment response of keloidal and hypertrophic sternotomy scars: comparison among intralesional corticosteroid, 5fluorouracil, and 585-nm flashlamppumped pulsed-dye laser treatments. Arch Dermatol 2002;138:1149–55. 5. Chan HH, Wong DS, Ho WS, et al. The use of pulsed dye laser for the prevention and treatment of hypertrophic scars in Chinese persons. Dermatol Surg 2004;30:987–94. 6. Lee TY, Chin GS, Kim WJ, et al. Expression of transforming growth factor beta 1, 2 and 3 proteins in keloids. Ann Plast Surg 1999;43:179–80. 7. Polo M, Smith DD, Kim YJ, et al. Effect of TGF-b2 on proliferative fibroblast cell kinetics. Ann Plast Surg 1999;43:185–90.
8. Kontochristopoulos G, Stefanaki C, Panagiotopoulos A, et al. Intralesional 5fluorouracil in the treatment of keloids: an open clinical and histopathologic study. J Am Acad Dermatol 2005 March;52:(3 Pt 1):474–9. 9. Ghoshal K, Jacob ST. An alternative molecular mechanism of action of 5-fluorouracil, a potent anti-cancer drug. Biochem Pharmacol 1997; 53:1569. 10. Blumenkranz MS, Claflin A, Hajek AS. Selection of the therapeutic agents for intra-ocular proliferative disease: cell culture evaluation. Arch Ophthalmol 1984;102:598–604. 11. Wendling J, Marchand A, Mauviel A, Verrecchia F. 5-Fluorouracil blocks transforming growth factor-beta-induced alpha 2 type I collagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 activation. Mol Pharmacol 2003; 64:707–13. 12. Kuo YR, Wu WS, Jeng SF, et al. Suppressed TGF-beta1 expression is correlated with up-regulation of matrix metalloproteinase-13 in keloid regression after flashlamp pulsed-dye laser treatment. Lasers Surg Med 2005;36:38–42. 13. 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;34:104–8. 14. Nanda S, Reddy BS. Intralesional 5-fluorouracil as a treatment modality of keloids. Dermatol Surg 2004; 30:54–7. 15. Ketchum LD, Cohen IK, Masters FW. Hypertrophic scars and keloids: a collective review. Plast Reconstr Surg 1974;53:140–54. 16. Friedman SJ, Butler DR, Dittelkov MR. Perilesional linear atrophy and hypopigmentation after intralesional corticosteroid therapy. J Am Acad Dermatol 1988;19:537–41. 17. Fitzpatrick RE. Treatment of inflamed hypertrophic scars using intralesional 5FU. Dermatol Surg 1999;25:224–32. 18. Uppal RS, Khan U, Kakar S, et al. The effects of a single dose of 5-fluorouracil on keloid scars: a clinical trial of timed wound irrigation after extralesional excision. Plast Reconstr Surg 2001;108:1218–24.
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19. Gupta S, Kalra A. Efficacy and safety of intralesional 5-fluorouracil in the treatment of keloids. Dermatology 2002; 204:130–2. 20. Shaffer JJ, Taylor SC, Cook-Bolden F. Keloid scars: a review with a critical look at therapeutic options. J Am Acad Dermatol 2002;46:Suppl:S63–97. 21. Apikian M, Goodman G. Intralesional 5fluorouracil in the treatment of keloid scars. Australas J Dermatol 2004;45: 140–3. 22. Reiken SR, Wolfort SF, Berthiaume F, et al. Control of hypertrophic scar growth using selective photothermolysis. Lasers Surg Med 1997;21:7–12. 23. Dierickx C, Goldman MP, Fitzpatrick RE. Laser treatment of erythematous/
hypertrophic and pigmented scars in 26 patients. Plast Reconstr Surg 199595:84– 90. 24. Alster TS, Williams CM. Treatment of keloid sternotomy scars with 585 nm flashlamp-pumped pulsed-dye laser. Lancet 1995;345: 1198–200. 25. Goldman MP, Fitzpatrick RE. Laser treatment of scars. Dermatol Surg 1995;21:685–7. 26. Wittenberg GP, Fabian BG, Bogomilsky JL, et al. Prospective, single-blind, randomized, controlled study to assess the efficacy of the 585-nm flashlamppumped pulsed-dye laser and silicone gel sheeting in hypertrophic scar treatment. Arch Dermatol 1999; 135:1049–55.
27. Allison KP, Kiernan MN, Waters RA, Clement RM. Pulsed dye laser treatment of burn scars: alleviation or irritation? Burns 2003;29:207–13. 28. Nouri K, Jimenez GP, Harrison-Balestra C, Elgart GW. 585-nm pulsed dye laser in the treatment of surgical scars starting on the suture removal day. Dermatol Surg 2003;29:65–73.
Address correspondence and reprint requests to: Afshin Darougheh, MD, Resident of Dermatology, Department of Dermatology, Isfahan University of Medical Sciences, Isfahan, Iran, or e-mail: darougheh@resident. mui.ac.ir.
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BACKGROUND Keloids and hypertrophic scars are benign growths of dermal collagen that usually cause major physical, psychological, and cosmetic problems. METHODS In this 12-week single-blinded clinical trial, 69 patients were randomly assigned into three study groups. In Group 1, intralesional triamcinolone acetonide (TAC, 10 mg/mL) was injected at weekly intervals for a total of 8 weeks. In Group 2 [TAC 1 5fluorouracil (5-FU)], 0.1 mL of 40 mg/mL TAC was added to 0.9 mL of 5-FU (50 mg/mL). This combination was injected weekly for 8 weeks. In Group 3, in addition to weekly TAC 1 5-FU injection for 8 weeks, lesions were irradiated by 585-nm flashlamp-pumped pulsed-dye laser (PDL, 5–7.5 J/cm 2) at the 1st, 4th, and 8th weeks. Lesions were assessed for erythema, pruritus, pliability, height, length, and width. RESULTS Sixty patients completed the study. At the 8- and 12-week follow-up visits, all groups showed an acceptable improvement in nearly all measures, but in comparison between groups, these were statistically more significant in the TAC 1 5-FU and TAC 1 5FU 1 PDL groups (po.05 for all). At the end of the study, the erythema score was significantly lower, and itch reduction was statistically higher in the TAC 1 5-FU 1 PDL group (po.05 for both). Good to excellent improvements (450% improvement) were reported by the patients as follows: 20% in Group 1, 55% in Group 2, and 75% in Group 3, all of which were significantly different (po.05). Good to excellent responses were reported by the blinded observer as follows: 15% in Group 1, 40% in Group 2, and 70% in Group 3. Their differences were statistically significant (po.05). Atrophy and telangiectasia were seen in 37% of patients in TAC group. CONCLUSION Overall efficacy of TAC 1 5-FU was comparable with TAC 1 5-FU 1 PDL, but the TAC 1 5-FU 1 PDL combination was more acceptable by the patients and produced better results. Its effect on lightening of the lesion was promising. The TAC 1 5-FU 1 PDL combination seems to be the best approach for treatment of keloid and hypertrophic scars. Ali Asilian, MD, Afshin Darougheh, MD, and Fazlolah Shariati, MD, have indicated no significant interest with commercial supporters.
K
eloids and hypertrophic scars are benign hyperproliferative growths of dermal collagen.1 Patients with these skin problems often experience major physical (deformities, restricted range of motion, pain, and pruritus) and psychological (cosmetic concern) problems.2
Although the basis for keloid and hypertrophic scar formation has not been fully delineated, it has been postulated that keloid- and hypertrophic scar–derived fibroblasts produce increased amounts of collagen per cell compared with normal fibroblasts.3 Thus, suppression of the overwhelming and uncontrolled fibroblast activity in
keloid and hypertrophic scar may be essential in therapeutic approaches to these abnormal wound responses.4 Increased vascularity has also occurred in keloid and hypertrophic scars.2,5 Transforming growth factor-b (TGF-b) has been implicated in the pathogenesis of the keloids.6,7
All authors are affilated with the Department of Dermatology, Isfahan University of Medical Sciences,
Isfahan, Iran & 2006 by the American Society for Dermatologic Surgery, Inc. Published by Blackwell Publishing ISSN: 1076-0512 Dermatol Surg 2006;32:907–915 DOI: 10.1111/j.1524-4725.2006.32195.x 907
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It is probably the combination of the proliferative scar fibroblasts’ abnormal response to TGF-b stimulation and elevated levels of this cytokine that is more important for keloid formation.8 There is no universally accepted treatment resulting in permanent hypertrophic or keloid scar ablation. Multiple modalities of treatment have been advocated. Most of these modalities have a variable and transient success. One of the long-term standards of keloid therapy, and the most commonly used therapeutic modality, is intralesional steroid injection. The corticosteroid inhibits a2-macroglobulin, which, in turn, inhibits collagenase. Once this pathway is blocked, collagenase is elaborated, thus enabling collagen degeneration.1 5-Fluorouracil (5-FU), a pyrimidine analog with antimetabolite activity, has been shown in tissue culture to inhibit fibroblast proliferation.9,10 It also has an inhibitory effect on TGF-b– induced type I collagen gene expression in human fibroblasts.11 The effect of flashlamp pulsed-dye laser (PDL) through selective damage of the microvasculature of the scar4 and down-regulation of TGF-b expression is also well known.12,13 With regard to these, in the present study the clinical response of keloid and hypertrophic scars is compared to treatment with intralesional triamcinolone acetonide (TAC) alone, TAC combined with 5-FU (TAC 1 5-FU), or TAC combined
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with 5-FU and 585-nm flashlamppumped PDL (TAC 1 5-FU 1 PDL).
Patients and Methods Study Design This is a 12-week, single-blinded, parallel-group, randomized clinical trial. The study protocol conformed to the guidelines of the 1975 Declaration of Helsinki and was approved by the review boards of dermatology department of St-Zahra Hospital (Isfahan, Iran) and Research Administration of Isfahan University of Medical Sciences. A total of 69 patients aged 5 to 70 years, who referred to Spadana Center of Dermatologic Consultation & Laser Therapy (Isfahan, Iran) were enrolled in this study. Informed consent was obtained from all subjects. All patients had complete blood cell counts along with renal and liver function tests checked before treatment as a baseline and at the end of the study. Patients who had previously been treated within the past 6 months, pregnant patients or patients planning pregnancy in the near future, lactating women, patients with chronic renal failure, or those showing any abnormalities of liver function tests or blood cell counts were excluded from the study. The lesions had to be a minimum of 10 mm in length. Only one lesion (preferably on the trunk or proximal extremities) per patient
was treated. They were randomly assigned in three study groups. In Group 1 (TAC), all patients were treated once weekly with intralesional TAC (10 mg/mL) for a total of eight sessions. In Group 2 (TAC 1 5-FU), 0.1 mL of 40 mg/ mL TAC was added to 0.9 mL of 5-FU (50 mg/mL). This combination was injected weekly for 8 weeks. In Group 3 (TAC 1 5-FU 1 PDL), in addition to eight weekly intralesional injections that were similar to Group 2, all patients were irradiated by a 585-nm PDL (Nlite System, EUPhotonics, Swansea, Wales, UK) with a pulse duration of 250 microseconds, at an energy density of 5 to 7.5 J/cm2 with a 5-mm spot and a single pass of spots overlapping 10% to 20% without cooling for three sessions at 1st, 4th, and 8th weeks. The solutions were injected into the body of the keloid using a 30gauge needle until slight blanching was clinically visible. The maximum volume of injection per square centimeter should not exceed 0.5 mL. The delivered dose was adjusted according to the extent of the lesions but did not exceed 2 mL per session. Only the firm portion of the keloid was treated by multiple injections, separated by approximately 1 cm. Assessments were carried out on the basis of patient satisfaction, observations, and measurements of a blinded observer (a derma-
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tology resident) and photographic records at the beginning and the 4th, 8th, and 12th weeks. At each assessment, the observer compared the photographs and measured the length, width, height, erythema, and pliability of the lesions. The observer also interviewed the patients and asked them about the symptoms and any adverse events encountered during the study. Evaluation Procedures Length, Width, and Height Scars were marked on every patient and mapped with a translucent paper at the first appointment to ensure the consistency of location. A dial caliper was used to determine greatest length, width, and height of the lesion (millimeter). Percentage of flattening was defined as the percentage of height reduction after treatment compared with baseline height (decrease in height/baseline height). Similar percentages were also defined for reduction in length and width. Erythema Erythema was graded by the observer on a 5-point scale as follows: 0 = no erythema; 1 = mild erythema; 2 = moderate erythema; 3 = severe erythema; and 4 = very severe erythema. Percentage of lesion lightening was defined as the percentage of erythema reduction compared with baseline erythema. Pliability Pliability was graded by the observer on a 5-point scale as follows: 0 = no induration; 1 = mild induration; 2 = moderate
induration; 3 = severe induration; and 4 = very severe induration. Percentage of lesion softening was defined as the percentage of pliability reduction compared with baseline pliability. Pruritus Severity of pruritus was graded by the patient on a 5-point scale as follows: 0 = no pruritus; 1 = mild pruritus; 2 = moderate pruritus; 3 = severe pruritus; and 4 = very severe pruritus. Percentage of itch reduction was defined as the percentage of pruritus reduction compared with baseline pruritus. Patient Self-Assessment At the 4th, 8th, and 12th weeks of the study, overall improvement was subjectively graded by patients on a 5-point scale as follows: no improvement; poor = up to 25% improvement; fair = 26% to 50% improvement; good = 51% to 75% improvement; and excellent = 76% to 100% improvement. Observer Assessment At the 4th, 8th, and 12th weeks of the study, overall improvement was graded by the observer by comparison of standardized photographs taken at 4-week intervals. Improvement scale was similar to patient selfassessment scale. Statistical Analysis Statistical analysis was carried out with computer software (SPSS 11.5 software for Windows, SPSS Inc., Chicago, IL, USA). Standard twotailed, paired t test analyses were performed within each study
group to compare means of each follow-up visit with the baseline. One-way analysis of variance, post hoc, and chi-square tests were performed to compare between three study groups at baseline, 4th, 8th, and 12th weeks. All statistical tests were two-tailed with a significance level of .05 (p o.05).
Results Baseline Characteristics Sixty of 69 patients who were enrolled into the study completed the full 12-week follow-up period. Sixty percent of the patients were female. Mean ages of the patients and mean duration of the lesions were 24.7 years (SD, 11.0 years) and 33.9 months (SD, 34.8 months), respectively. The site distribution was as follows: 38.5% on the face and neck, 35% on the trunk, 21.7% on proximal extremities, and 5% on distal extremities. At baseline, there were no statistically significant differences in means of age, duration, length, width, height, erythema, pruritus, and pliability between all study groups (Table 1).
Length, Width, and Height In comparison with the baseline, there was a statistically significant decrease in length, width, and height in all three study groups at the 4th, 8th, and 12th weeks (po .05 for all). There were only two
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TABLE 1. Demographic Features and Baseline Characteristics Group 1
Group 2
Group 3
Variable
(TAC)
(TAC 1 5-FU)
(TAC 1 5-FU 1 PDL)
p Valuey
Gender (male/female), No. (%) Age (years) Duration(months) Length (mm) Width (mm) Height (mm) Erythema score Pliability score Pruritus score
7/13 23.4 12.6 34.1 12.7 3.7 3.0 2.4 2.6
8/12 25.3 12.2 36.9 12.7 3.3 3.3 2.5 2.4
9/11 25.5 11.6 33.1 10.0 3.4 3.2 2.8 2.6
.812 .816 .910 .952 .633 .820 .574 .386 .838
(35/65) (8.0) (7.4) (26.7) (11.3) (1.9) (1.0) (1.0) (1.3)
(40/60) (11.9) (7.3) (50.27) (11.8) (1.6) (0.7) (1.0) (1.8)
(45/55) (13.0) (6.0) (37.6) (6.4) (2.8) (1.1) (0.8) (1.5)
Data are reported as mean 7 SD. y
All p values were greater than .05 (no statistically significant differences between groups were determined).
In comparison between three groups at the 4th and 12th weeks, percentage of length reduction in the TAC 1 5-FU and TAC 1 5-FU 1 PDL groups was statistically more than in TAC group (po.05 for both). Percentage of width reduction in the TAC 1 5-FU group at the 4th week was statistically more than both other groups (po.05 for both). In contrast, at the 8th and 12th weeks, higher percentages of width reduction were observed in both the TAC 1 5-FU and the TAC 1 5-FU 1 PDL groups, compared to the TAC group (pr.001 for both).
(po.05; Figure 1). Percentages of lesion flattening at the 4th, 8th, and 12th weeks were statistically higher in the TAC 1 5-FU and TAC 1 5-FU 1 PDL groups, compared with the TAC group (po .01 for all). At the end of the study, the average lesion flattened 50, 77, and 79% in Groups 1, 2, and 3, respectively. Erythema The decrease in erythema score was statistically significant in all
study groups during all follow-up visits (po.05 for all). In comparison between three study groups at the 8th week, the erythema score in the TAC group was significantly higher than the TAC 1 5-FU and TAC 1 5-FU 1 PDL groups (po.05 for both). At the end of the study, this measure in the TAC 1 5-FU 1 PDL group was significantly lower than the TAC and TAC 1 5-FU groups (po.05 for both) (Figure 2). Higher percentages of lesion
5 4.5 4
3.7
3.5
3.5 Height (mm)
exceptions; both of them were in the TAC group. The first was decrease in height at the 4th week, and the second was decrease in length at the 8th week.
3
3.4
3.3
3.2 2.6
baseline 4th week 8th week 12th week 2.8
2.5
2.5 1.8
1.7
2 1.5
1.2
1.2
1 0.5
Lower mean heights of lesions were observed at the 8th and 12th weeks in the TAC 1 5-FU and TAC 1 5-FU 1 PDL groups
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0 TAC
TAC+5-FU Group
TAC+5-FU+PDL
Figure 1. Mean lesion height reduction during 12-week follow-up.
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4 3.5
Erythema score
3
3.3 3 3 2.7
baseline 4th week 8th week 12th week
3.2 3
2.9
2.5 1.9
2
2
Observer Assessment
2 1.7
1.5
group (po.05). At the same visit, percentage of itch reduction in Group 3 was significantly greater than in the TAC group (po.05).
At the last visit, the highest and lowest improvements were observed in the TAC 1 5-FU 1 PDL and TAC groups, respectively (Figure 5). Their differences were statistically significant (po.05). At the same visit, good to excellent response observed as follows: 15% in the TAC group, 40% in the TAC 1 5-FU group, and 70% in the TAC 1 5-FU 1 PDL group, all of which were significantly different (po.05).
Patient Self-Assessment
Adverse Events
At the end of the study, patient self-assessment was highest in the TAC 1 5-FU 1 PDL group and lowest in the TAC group (Figures 3 and 4). Their differences were statistically significant (po.05). At the same visit, good to excellent improvement (improvement of 50% or higher) was reported by the patients as follows: 20% in the TAC group, 55% in the TAC 1 5-FU group, and 75% in
During the study, no abnormalities were detected in the laboratory data. Nearly all injections were painful. In the TAC group, 37% of patients reported some degree of skin atrophy and telangiectasia.
1.2
1 0.5 0 TAC
TAC+5-FU TAC+5-FU+PDL Group
Figure 2. Decrease in erythema score during 12-week follow-up.
lightening at the 8th and 12th weeks were found in both the TAC 1 5-FU and the TAC 1 5-FU 1 PDL groups, compared with the TAC group, both of which were statistically significant (po.05 for all). Pliability A statistically significant softening of lesions versus baseline was observed in all three study groups at the 8th and 12th weeks (po.05 for all). Improvement in pliability was also progressive. In comparison between groups, however, pliability scores and percentages of softening were not significantly different.
the TAC 1 5-FU 1 PDL group, all of which were significantly different (po.05).
In the TAC 1 5-FU 1 PDL group, the areas treated with the PDL became purpuric, which lasted from 7 to 10 days. On conclusion
Pruritus Severity of pruritus was significantly decreased versus baseline in all study groups at all follow-up visits (po.05 for all). At the 12th week, there was a statistically significant decrease in pruritus score in the TAC 1 5-FU 1 PDL group compared with the TAC
Figure 3. Burn scars of a patient in the TAC 1 5-FU 1 PDL group before and after treatment.
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100
not improved poor response fair response good response excellent response
90
% of patients
80 70
60 55
60
55
45
50 40 30
20
20
20
15
20
10
10 0 TAC
TAC+5-FU Group
TAC+5-FU+PDL
Figure 4. Patient self-assessment at the end of the study.
of the study, neither adverse textural nor pigmentary alterations were observed in either the TAC 1 5-FU or the TAC 1 5-FU 1 PDL group. Ulcers or erosions were also not seen.
Discussion The efficacy of corticosteroid injections in the treatment of keloids and hypertrophic scars has been well established. The most commonly used corticosteroid is TAC. The dosage and treatment interval have arbitrarily varied
from 10 to 40 mg/mL administered at intervals of 4 to 6 weeks for several months or until the scar is flattened. Although intralesional TAC administration has shown 50% to 100% clinical efficacy,14 the outcome has been uncertain and associated with multiple adverse effects, including atrophy, telangiectasia, and pigmentary changes, which are not acceptable adverse effects for most patients.15,16 In the present study, even though all indices in TAC group were improved, patient self-assessment and observer
100
not improved poor improvement fair improvement good improvement excellent improvement
90
% of patients
80 70
60
60
55
50
50 40
35
30
30
20 15
20 10
5
5
15
10
0 TAC
TAC+5-FU Group
TAC+5-FU+PDL
Figure 5. Observer assessment at the end of the study.
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assessment were only 20 and 15%, respectively. These relatively low improvements are probably related to relatively short follow-up duration (12 weeks). The rate of adverse reaction in this group was approximately equal to that in the study by Manuskiatti and colleagues,4 which was 40%. Fitzpatrick17 was the first who reported his 9-year experience administering more than 5,000 injections to more than 1,000 patients. He found that by mixing 1 mg/mL TAC with the 5-FU (by adding 0.1 mL of 10 mg/mL TAC to 0.9 mL of 50 mg/mL 5-FU), efficacy was improved and injections were less painful. Patients returned for injections a mean of 5 to 10 times. Fibroblast regression is dependent on the duration of exposure to the drug and the dose.18 It has been found that 5FU delivered intralesionally once weekly or once every 2 weeks in keloids and hypertrophic scars is effective.4,17,19 All the literature relating to the role of corticosteroids in keloid therapy suggests that a dose of 10 to 40 mg/mL TAC is required to be effective in keloid or hypertrophic scars.20 The mixture of corticosteroid used in TAC 1 5-FU combination would result in a concentration equivalent to 4 mg/ mL triamcinolone, which would not be expected to have any efficacy in treatment of patients. It was employed for its effect on potential 5-FU–induced inflammation.21
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The results of our study in the TAC 1 5-FU group are comparable to those reported previously.14,17 Nanda and Reddy14 reported that almost 80% of their patients showed more than 50% improvement. Again, lower improvement in our study is probably related to short follow-up period. In comparison with TAC group, it seems that TAC 1 5-FU combination is more effective and provides a more rapid response with few if not at all side effects. Our results are in line with that of Apikian and Goodman21 who found that intralesional 5-FU mixed with low-dose corticosteroid may be a possible alternative for the treatment of keloid scars and may have fewer undesirable side effects when compared with intralesional potent corticosteroids alone. Comparable results have been reported by other investigators.4,19,20 As Nanda and Reddy14 said, at the end of our study there were no serious systemic side effects in Groups 2 and 3. Systemic 5-FU can cause anemia, leukopenia, and thrombocytopenia. Even though 90 mg of 5-FU was not exceeded at each injection session, the use of higher doses has been reported without development of any adverse hematologic effects.17,19 The effectiveness of PDL in the treatment of keloids and hypertrophic scars is controversial. It
has been thought to be mediated by selective damage of the microvasculature of the scar.22 Dierickx and coworkers23 used a 585-nm PDL (6–7.5 J/cm2, 5-mm spot size) to treat hypertrophic scars, and after a mean number of 1.8 treatment sessions, the mean degree of improvement as judged by the treating physician was 77%.23 In some patients whose scars responded to TAC 1 5-FU injections, PDL was added by Fitzpatrick17 to eliminate residual erythema. Alster and Williams24 treated 16 patients with sternotomy scars by PDL and detected significant degrees of improvement in terms of color and skin thickness. A mean improvement in nonfacial scars of 81% after 2 1/2 treatments with PDL was reported by Goldman and Fitzpatrick.25 These positive results were confirmed by Manuskiatti and colleagues.2 In addition, they noted a significantly higher percentage of scar flattening after more than two treatments. In contrast, Wittenberg and associates,26 in the study of the efficacy of the 585-nm PDL in treatment of hypertrophic scars, showed that the clinical improvement in scar sections treated with four PDL irradiations at 8-week intervals was no different than that in control sections. More recently, another controlled study using PDL indicated that although patients’ pruritus improved, the reduction in terms of erythema or scar thickness was insignificant.27 These observations are consistent with data of Chan and colleagues5
that indicated that although most of the patients reported improvement, objective assessment did not indicate significant changes once the changes in the control sections were taken into consideration. Nouri and coworkers28 examined the role of PDL (10-mm spot size and a fluence of 3.5 J/cm2) in the treatment of surgical scars, and they suggested that scar location can have an effect on facial, shoulder, and arms scars, which respond better than those in the anterior chest walls. Reiken and associates22 reported a fluence-dependent inhibition of hypertrophic scar implants in mice that was proportional to the fluence from 6 to 10 J/cm2 using a candela PDL. In contrast, previous clinical studies on the PDL treatment of scars noted no significant difference in the treatment outcome versus minor variations in fluence used (6.0– 7.5 J/cm2).23,25 Similarly, Manuskiatti and associates2 noted no statistically significant fluence dependence of the clinical improvement of keloid and hypertrophic scars after PDL treatment. A trend toward better response with lower fluence was observed, however. A recent review article suggested that the fluence to be used for the treatment of hypertrophic scars should range from 4.5 to 7.5 J/ cm2, depending on the spot size (5–10 mm with higher fluence used for smaller spot size).5 Therefore, the authors treated our
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patients with 5 to 7.5 J/cm2 (5mm spot size) for three sessions and 70% to 75% of them showed more than 50% improvement. It seems that the difference in results can be due to several factors. Some of them are scar location and duration, different laser settings, skin types, follow-up duration, and subjective or objective assessments. Our follow-up period was only 12 weeks. As Manuskiatti and Fitzpatrick4 said, continuous improvement was sustained even 10 to 12 weeks after the end of their study. Perhaps multiple sequential laser treatments and longer follow-up may be essential for achieving a better clinical response. In comparison with TAC and TAC 1 5-FU groups, the TAC 1 5-FU 1 PDL combination is more effective and provides a more rapid response with few side effects. This results in a relatively short treatment period indicating that this combination may have a synergistic effect on keloid and hypertrophic scars. In conclusion, it must be said that it is the first randomized clinical trial that compares the TAC 1 5-FU 1 PDL combination with TAC alone or TAC 1 5-FU in treatment of keloid and hypertrophic scars. Both subjective and objective assessments were used to evaluate the efficacy of these modalities. Even though all treatment groups in our study showed an acceptable improvement in nearly
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all measures, these were more significant in the TAC 1 5-FU 1 PDL group. This combination was also more acceptable by the patients. Its effect on itch reduction and lightening of the lesion was promising. The TAC 1 5-FU 1 PDL combination seems to be the best approach for treatment of keloid and hypertrophic scars.
Acknowledgment We are very grateful to personnel of Spadana Center of Dermatologic Consultation & Laser Therapy for their help in our research.
References 1. Kelly AP. Medical and surgical therapies for keloids. Dermatol Ther 2004;17: 212–8. 2. Manuskiatti W, Fitzpatrick RE, Goldman MP. Energy density and numbers of treatment affect response of keloidal and hypertrophic sternotomy scars to the 585-nm flashlamp-pumped pulsed-dye laser. J Am Acad Dermatol 2001;45: 557–65. 3. Tuan T, Nichter LS. The molecular basis of keloid and hypertrophic scar formation. Mol Med Today 1998;4:19–24. 4. Manuskiatti W, Fitzpatrick RE. Treatment response of keloidal and hypertrophic sternotomy scars: comparison among intralesional corticosteroid, 5fluorouracil, and 585-nm flashlamppumped pulsed-dye laser treatments. Arch Dermatol 2002;138:1149–55. 5. Chan HH, Wong DS, Ho WS, et al. The use of pulsed dye laser for the prevention and treatment of hypertrophic scars in Chinese persons. Dermatol Surg 2004;30:987–94. 6. Lee TY, Chin GS, Kim WJ, et al. Expression of transforming growth factor beta 1, 2 and 3 proteins in keloids. Ann Plast Surg 1999;43:179–80. 7. Polo M, Smith DD, Kim YJ, et al. Effect of TGF-b2 on proliferative fibroblast cell kinetics. Ann Plast Surg 1999;43:185–90.
8. Kontochristopoulos G, Stefanaki C, Panagiotopoulos A, et al. Intralesional 5fluorouracil in the treatment of keloids: an open clinical and histopathologic study. J Am Acad Dermatol 2005 March;52:(3 Pt 1):474–9. 9. Ghoshal K, Jacob ST. An alternative molecular mechanism of action of 5-fluorouracil, a potent anti-cancer drug. Biochem Pharmacol 1997; 53:1569. 10. Blumenkranz MS, Claflin A, Hajek AS. Selection of the therapeutic agents for intra-ocular proliferative disease: cell culture evaluation. Arch Ophthalmol 1984;102:598–604. 11. Wendling J, Marchand A, Mauviel A, Verrecchia F. 5-Fluorouracil blocks transforming growth factor-beta-induced alpha 2 type I collagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 activation. Mol Pharmacol 2003; 64:707–13. 12. Kuo YR, Wu WS, Jeng SF, et al. Suppressed TGF-beta1 expression is correlated with up-regulation of matrix metalloproteinase-13 in keloid regression after flashlamp pulsed-dye laser treatment. Lasers Surg Med 2005;36:38–42. 13. 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;34:104–8. 14. Nanda S, Reddy BS. Intralesional 5-fluorouracil as a treatment modality of keloids. Dermatol Surg 2004; 30:54–7. 15. Ketchum LD, Cohen IK, Masters FW. Hypertrophic scars and keloids: a collective review. Plast Reconstr Surg 1974;53:140–54. 16. Friedman SJ, Butler DR, Dittelkov MR. Perilesional linear atrophy and hypopigmentation after intralesional corticosteroid therapy. J Am Acad Dermatol 1988;19:537–41. 17. Fitzpatrick RE. Treatment of inflamed hypertrophic scars using intralesional 5FU. Dermatol Surg 1999;25:224–32. 18. Uppal RS, Khan U, Kakar S, et al. The effects of a single dose of 5-fluorouracil on keloid scars: a clinical trial of timed wound irrigation after extralesional excision. Plast Reconstr Surg 2001;108:1218–24.
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19. Gupta S, Kalra A. Efficacy and safety of intralesional 5-fluorouracil in the treatment of keloids. Dermatology 2002; 204:130–2. 20. Shaffer JJ, Taylor SC, Cook-Bolden F. Keloid scars: a review with a critical look at therapeutic options. J Am Acad Dermatol 2002;46:Suppl:S63–97. 21. Apikian M, Goodman G. Intralesional 5fluorouracil in the treatment of keloid scars. Australas J Dermatol 2004;45: 140–3. 22. Reiken SR, Wolfort SF, Berthiaume F, et al. Control of hypertrophic scar growth using selective photothermolysis. Lasers Surg Med 1997;21:7–12. 23. Dierickx C, Goldman MP, Fitzpatrick RE. Laser treatment of erythematous/
hypertrophic and pigmented scars in 26 patients. Plast Reconstr Surg 199595:84– 90. 24. Alster TS, Williams CM. Treatment of keloid sternotomy scars with 585 nm flashlamp-pumped pulsed-dye laser. Lancet 1995;345: 1198–200. 25. Goldman MP, Fitzpatrick RE. Laser treatment of scars. Dermatol Surg 1995;21:685–7. 26. Wittenberg GP, Fabian BG, Bogomilsky JL, et al. Prospective, single-blind, randomized, controlled study to assess the efficacy of the 585-nm flashlamppumped pulsed-dye laser and silicone gel sheeting in hypertrophic scar treatment. Arch Dermatol 1999; 135:1049–55.
27. Allison KP, Kiernan MN, Waters RA, Clement RM. Pulsed dye laser treatment of burn scars: alleviation or irritation? Burns 2003;29:207–13. 28. Nouri K, Jimenez GP, Harrison-Balestra C, Elgart GW. 585-nm pulsed dye laser in the treatment of surgical scars starting on the suture removal day. Dermatol Surg 2003;29:65–73.
Address correspondence and reprint requests to: Afshin Darougheh, MD, Resident of Dermatology, Department of Dermatology, Isfahan University of Medical Sciences, Isfahan, Iran, or e-mail: darougheh@resident. mui.ac.ir.
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