Efficacy of fractional CO 2 laser with intralesional steroid compared with intralesional steroid alone in the treatment of keloids and hypertrophic scars

Summary: Background and objective: Keloids and hypertrophic scars (HTS) are abnormal fibrous reactions that persist for prolonged periods, rarely regress without treatment and recur after excision. Many modalities of treatment have been advocated but the success rates of these have been variable. The present study is an attempt to evaluate and compare the efficacy of combination of fractional CO2 laser (FCL) and intralesional steroid (ILS) against ILS alone in the treatment of keloids and HTS. Methods: Patients with keloids or HTS were divided into two groups of 25 each receiving four sessions of therapy. Group 1 (FCL + ILS) received combination of FCL and intralesional triamcinolone acetonide (TAC) 10 mg/mL. Group 2 (ILS only) received intralesional TAC 10 mg/mL alone. Pretreatment measurements and photographs were taken. Two unbiased qualified dermatologists made independent evaluation of the photographs using modified Manchester quartile score (MQS). The patient's satisfaction to treatment was graded on a scale of 1‐4. Statistical analysis was done using a statistical software. Results: Statistically significant improvement was seen in height and length of the lesions. Overall appearance criteria of modified MQS showed an improvement of more than 50% in 43.3% of the lesions by the end of four sessions. Degree of hypertrophy showed more than 50% improvement in 40% of the lesions treated. Dyschromia showed more than 50% improvement in 33.4%. Texture showed the least improvement, with only 30% of lesions showing an improvement of more than 50%. The improvement of these parameters in ILS only group was significantly lower than the improvement seen in the FCL + ILS group. Conclusion: Combination therapy with FCL and ILS was superior in efficacy when compared to ILS alone, in the treatment of keloids and HTS.

Keywords: fractional CO2 laser; hypertrophic scars; intralesional triamcinolone acetonide; keloid

Keloids and hypertrophic scars (HTS) are abnormal fibrous reactions to trauma, inflammation, surgery, or burns. They frequently occur in the age‐group of 10‐30 years. Areas of highest skin tension like the upper back, shoulders, anterior chest, and upper arms are commonly affected by them.[1] Patients experience pain, pruritus, restricted range of movements, and psychological problems due to cosmetic concern.[2] Keloids are distinguished from HTS by their extension beyond the original sites of trauma, persistence for a prolonged period, rare resolution without treatment, and recurrence after excision. HTS do not extend beyond the initial site of injury and slowly reduce in size, ultimately resolving over a period with low recurrence rates.[3] HTS and keloids are a challenge for the treating physician because of the weak response to treatment, recurrences after treatment, and side effects associated with the treatment modalities.[[4]] There is no universally accepted method of treatment, which will lead to complete resolution of HTS or keloids. Many modalities of treatment have been advocated but the success rates of these are variable. Intralesional steroid (ILS) has been one of the most commonly used treatment modalities in keloid therapy.[2] When intralesional steroid was combined with other modalities like 5 fluorouracil and ablative fractional CO2 laser (FCL), it produced a better result compared to intralesional steroid alone.[[4], [6]]

Recent advances in laser technology have provided newer options for improvement in function, symptoms, and cosmetic appearance of keloids and HTS. FCL therapy leads to the formation of zones of ablation at variable depths of the skin with the subsequent response involving wound healing and collagen remodeling.[4] Carbon dioxide laser ablation has been found to act on fibroblasts in vitro by stimulating basic fibroblast growth factor (bFGF) and inhibiting transforming growth factor‐β1 (TGF‐β1), which may lead to normalized wound healing. Thus, carbon dioxide laser ablation has been suggested to be useful in the treatment of keloids.[8]

Objectives of our study were as follows:

• To evaluate the efficacy and safety of combined FCL and intralesional triamcinolone acetonide (TAC) in the treatment of keloids and HTS.
• To evaluate the efficacy and safety of intralesional TAC in the treatment of keloids and HTS.
• To compare the efficacy of FCL with intralesional TAC against intralesional TAC alone in the treatment of keloids and HTS.

This was a hospital‐based comparison study which included all patients attending the outpatient Department of Dermatology in Justice K.S Hegde Charitable hospital, Mangalore, India, diagnosed clinically to have keloids or HTS and who had satisfied the inclusion and exclusion criteria laid down for the study. Institutional ethics committee clearance was obtained before starting the study.

• Age >18 years.
• All clinically diagnosed cases of keloid and HTS.
• Patients who gave their informed consent.

• Patients not consenting to participate in the study.
• Patients who were pregnant or lactating.
• Patients with history of intake of oral retinoids in the past 6 months.
• Patients with signs of active infection or lesions suspicious of malignancy.

The patients were initially counseled regarding the nature of the present study and offered the choice of therapy between either combined FCL and intralesional TAC (IL‐TAC) or intralesional TAC alone without laser therapy. Thus, two groups were formed; one group (FCL + ILS) who underwent treatment with FCL followed by intralesional TAC 10 mg/mL and the other group (ILS only) where only intralesional TAC 10 mg/mL was given. Informed consent was taken and a detailed history was obtained and recorded in a structured proforma with details about the lesion, any significant past or present history, general physical examination as well as cutaneous examination. The length, breadth and height of the keloids or HTS were measured using a vernier caliper, which measures up to 200 mm length with a one cm dial for increased accuracy.

Baseline photographs were taken. After photographs were taken, any hair in the area to be treated were trimmed but not shaved and topical anaesthetic was applied for a minimum period of 45 minutes. In our study, eutectic mixture of prilocaine and lignocaine was used as the topical anaesthetic. After the desired time for anaesthesia elapsed, the area was cleaned off the topical anaesthetic and was prepared using povidone‐iodine solution. Patient's eyes were covered using protective metallic eye shields, and preprocedure cooling was done with ice cubes. After this, lasing of keloids and HTS was done with FCL.

The CO2 laser used for our study was a super pulse and continuous wave enabled CO2 laser system (Acupulse from Lumenis). The combo mode was used for treatment, where there was firing of both deep and superficial components in the same press of the footswitch. The delivery of the patterns were sequentially controlled, with the deep scan being fired first followed by firing of the superficial scan after a short pause of 500 milliseconds. In our study, the parameters used most often ranged from 5 to 30 mJ of energy and 5% to 30% density for deep scan and an energy of 50‐80 mJ and a density ranging from 40% to 60% for the superficial scan. Laser beams of various shapes were used which included square, hexagonal or line for various shapes and areas of keloids and HTS, based on suitability and convenience. Single pass was given to all the patients selected.

Postprocedure cooling was done following the laser treatment. Systemic antibiotic, azithromycin 500 mg once a day for 3 days, and topical antibacterial cream containing fusidic acid for a week were prescribed. Intralesional injection of TAC 10 mg/mL was given via a 2 cc syringe mounted with a 26 gauge needle. Patients were instructed to come back after a period of 28 days for the next session.

A minimum of four such sessions were advised to the patients for the purpose of this study. At every session, pretreatment photographs were taken under identical camera and lighting conditions and measurements were recorded for both the groups.

At the end of the four sessions, the patients were asked to rate the level of improvement they felt on a scale of 1‐4 where, grade 1—none; 2—fair; 3—good; 4—very good.

Two unbiased qualified dermatologists, unrelated to the study and the institute, made independent clinical and photographic assessment to evaluate the improvement in overall appearance, dyschromia, degree of hypertrophy, and texture using modified Manchester quartile score (MQS)[4]. The following four‐point scale was utilized:

• 0—less than 25% improvement.

1—25%‐50% improvement.

• 2—50%‐75% improvement.
• 3—more than 75% improvement.

For each patient, scores in each category were then averaged to assign an overall score.

The data were statistically analyzed using mean, median, standard deviation, the confidence interval, and coefficient of variation for comparing the scores of the patients under each study group. Chi‐square/Fishers exact test was used to assess the statistical significance of various parameters given in patient's data. Scores and values obtained for the two study groups were compared using Mann‐Whitney U test. Spearman's rho test was used to compare patient satisfaction score and the improvement. A P‐value <0.05 was considered to be statistically significant with outcome. SPSS version 16 (SPSS Inc, Chicago, IL) was used to analyze the data.

In this comparative study, a total of 75 patients with keloids and HTS were enrolled. Fifty subjects completed the study requirements and remaining 25 did not. The reasons for exclusion of the 25 patients include not completing the required four sessions, financial constraints, unrealistic expectations even after pretreatment counseling and travelling from far‐off places to the hospital. Of the 50 subjects enrolled, 25 patients received laser therapy followed by intralesional injection (FCL + ILS group) and other 25 patients received intralesional injections alone (ILS only group). There were 56 lesions in total in 50 patients, with six patients having more than one lesion. FCL + ILS group had 30 lesions, whereas ILS only group had 26 lesions. Demographic profile of patients and features of pathological scars is given in Tables and , respectively.

Demographic profile of study subjects

1 LC, lower class; MC, middle class; UC, upperclass.

Features of pathological scars

Majority (82.1%) of the lesions were classified as keloids, while 17.9% were classified as HTS. Duration of the lesions ranged from 6 months to 20 years. Most of the lesions were present for a duration of 1‐3 years, seen in 39.3% (22/56) of the lesions. A duration of 4‐6 years was observed in 21.4% (12/56) of lesions. Most (69.64%) of the lesions occurred as a result of trauma, while 16.07% of lesions occurred secondary to acne and 14.28% of lesions occurred spontaneously. Of the 69.64% of lesions following trauma, 76.92% were seen in males and the rest in females. Twenty‐five (44.64%) lesions had received some form of treatment prior to the start of this study, which included use of topical application of creams (7.1%), intralesional injections (17.1%), cryotherapy (8.9%), laser (8.9%), and surgery (1.8%). Symptoms at the time of presentation included itching, pain, or both. Previous treatments and associated symptoms are given in Table. Patients who had undergone intralesional steroid and cryotherapy opted for combination therapy which showed statistical significance. We also found the influence of severity of associated symptoms on choice of treatment was not statistically meaningful. Relief of symptoms associated with the lesions following therapy was seen in 28.9% (13/45) of the lesions and mostly in the FCL+ILS group. Thirteen (23.21%) lesions had adverse effects, which included increase in size (5/13), pain (4/13), hyperpigmentation (2/13), and depigmentation (2/13). Adverse effects were more frequent in the FCL+ILS group (10/56; 17.86%) compared to the ILS only group (3/56; 5.36%). Adverse effects are given in Table. On analyzing post‐treatment dimensions of keloid/HTS between the groups, a statistically significant reduction in height (P = 0.003) and length (P = 0.025) was observed. No significant improvement in breadth (P = 0.902) was observed. Pre‐ and post‐treatment dimensions are given in Table.

Previous treatment and associated symptoms

2 P < 0.05 is considered significant.

Adverse effects

Pre‐ and post‐treatment dimensions of the HTS and keloids

3 B, breadth; H, height; L, length.

Intra‐class correlation coefficient was taken to see whether any interobserver variation was present between the two observers in each session. It was interpreted as follows; <0.40: poor agreement, 0.40‐0.75: fair agreement, 0.75‐0.85: good agreement, and >0.85: excellent agreement.

It was found that both the observers had a fair to good agreement in their assessment. Comparing FCL+ILS group against ILS only group in each session with respect to every parameter of the modified MQS, showed statistically significant improvement in FCL+ILS group as against ILS only group in all the four parameters (Table ; Figures and : FCL + IL‐TAC in a 22‐year‐old man before and after therapy; Figures and : FCL+IL‐TAC in a 46‐year‐old woman before and after therapy).

Modified MQS across consecutive sessions in both the groups

4 DOH, degree of hypertrophy; DYS, dyschromia; OAA, overall appearance; HS, highly significant; TEX, texture.

It was found that the patient satisfaction was highest in FCL+ILS group compared to ILS only group and it was statistically significant (P = 0.003). When patient satisfaction was correlated with parameters of modified MQS using Spearman's rho test, significant positive correlation was observed between the modified MQS parameters and the scores. When length, breadth, and height were correlated with patient satisfaction scores, only length showed moderately positive correlation (Table).

Correlation of PSS with length, breadth, height, and modified MQS parameters

5 B, breadth; DOH, degree of hypertrophy; DYS, dyschromia; H, height; L, length; OAA, overall appearance; PSS, patient satisfaction scale; TEX, texture. P < 0.05 is considered significant.

Manstein and his colleagues in the year 2004 introduced the modality of fractional lasers in dermatology and concluded that it was a favorable mode of treatment in all skin types and that they presented the potential in the use of scars and acne.[9] FCL with a wavelength of 10 600 nm has minimal side effects and causes a decrease in TGF‐β1 and increase in bFGF resulting in dermal collagen changes.[[10]] Nowak et al[12] reported release of bFGF and inhibition of TGF‐β1 from both normal and keloidal cells following exposure to superpulsed CO2. The combined effect of these two will result in reduction in thickness and improvement in appearance of keloid. A study on burn scars treated with FCLs found improvement in pliability of HTS also.[13] In our study, the lesions showed improvement over the sessions with a statistically significant improvement in length and flattening in height in FCL+ILS group as against ILS only group while no such significance was seen in the breadth of these lesions. Among the modified MQS parameters assessed, it was found that overall appearance parameter showed an improvement of more than 50% in 43.3% of the lesions. Degree of hypertrophy showed more than 50% improvement in 40% of the lesions treated. Dyschromia showed more than 50% improvement in 33.4% while texture was the least improved parameter with only 30% of lesions showing an improvement of more than 50%. Combination therapy of FCL with intralesional triamcinolone acetonide (IL‐TAC) was significantly superior in efficacy compared to IL‐TAC used alone. Waibel et al evaluated the efficacy of a combination therapy of ablative FCL with topical application of TAC suspension in the immediate postoperative period on 15 patients with keloids and HTS found 80% of patients had improvement of more than 75% in texture and 73% showed an improvement of more than 75% in degree of hypertrophy while only 47% showed an improvement of more than 75% in dyschromia. The improvement in overall appearance of more than 75% was seen in 73%. Majority of these patients were of Fitzpatrick skin type 2‐4. Also this study did not report any adverse effects following the end of the study.[4] Small sample size was a limiting factor of this study. Another study assessed the effects of FCL on patients with HTS and found textural improvement in all with minimal side effects.[14]

With regard to adverse effects following therapy, 23.21% presented with some form of side effects in our study. Though FCL+ILS group had more side effects compared to ILS only group, it was not statistically significant (P = 0.0653). The most common adverse effect encountered was regrowth of the lesion, seen in 8.9%[5] lesions, which was slightly higher in the FCL+ILS group (3/5) compared to ILS only group (2/5). All five lesions were seen in males and were located on the chest. Since the chest is a high tension region with high mobility, we speculate that continued hard labor during the interval between the sessions could have altered the positive effects of the treatment. We believe this could have been overcome with more number of sessions and adequate rest between the sessions. Last but not the least factor to consider is refractoriness to treatment of keloid, which could have continued in its growth phase in spite of treatment. Acute postprocedure effects like pain and edema, which were mild in intensity, were seen in almost all the patients and were managed by ice packs. Persistent pain was seen in 7.14%. It was managed with diclofenac tablet 50 mg twice a day for 2‐3 days. Hyperpigmentation was noticed in only 3.8% of cases in our study, even though all our patients were of Fitzpatrick skin types 4 to 5. It was exclusively seen in the FCL+ILS group receiving laser therapy and intralesional injection. The presence of majority of these lesions in covered areas and sufficient cooling during and after procedure could have been the contributory factors for this finding. El‐Zawahry et al, in his study of ablative CO2 fractional resurfacing on postburn scars, found 33.3% of cases developed hyperpigmentation as an adverse effect after laser therapy. They also reported all of these cases improved on applying bleaching cream for 4 weeks.[15] Depigmentation was seen in 3.8% of lesions in both FCL+ILS group and ILS only group with similar frequency, and this may be due to the intralesional steroid injection. Garg et al, in their study, reported 14.29% of lesions developing depigmentation secondary to intralesional steroid injection.[16] In our study, both the groups received intralesional steroid of the same dose (Figures and : adverse effects before and after FCL+IL‐TAC therapy, respectively; Figures and : before and after IL‐TAC therapy alone, respectively).

Taking the benefits into consideration and also considering the fact that the above‐mentioned adverse effects are transient, treatable, or inconsequential to the patient and may improve with further sessions, we conclude that the combination therapy (FCL+ILS) was useful and gave better results compared to ILS alone in the treatment of HTS and keloids.

Small sample size—This study included 25 cases and 25 controls. A larger sample size would have shed more light on the role of lasers and combination therapy.

Limited number of sessions—In our study, there were only 4 sessions of treatment at an interval of 28 days and therefore unable to assess the overall effect that more number of sessions would have had.

Some of the lesions were previously treated with some form of treatment; therefore, the improvement noticed in these lesions could be a compounded effect of the previous treatment.

Lack of long‐term follow‐up—The patients who completed the study were lost to follow‐up. As a result, lesions that showed little or good improvement at the end of the 4th session could have improved or showed regrowth following the end of this study.

Nil.