Comparison of surgical excision followed by adjuvant radiotherapy and laser combined with steroids for the treatment of keloids: A systematic review and meta‐analysis

Abstract

This meta‐analysis aims to evaluate and compare the effect of surgical excision followed by adjuvant radiotherapy and laser combined with steroids on keloids. Relevant studies reporting the recurrence rate or incidence of adverse events (AEs) were retrieved from the PubMed, Web of Science, Embase and Cochrane Library databases through August 2023. The quality of noncomparative single‐arm clinical trials was evaluated using the methodological index for nonrandomised studies (MINORS) Methodological items. This meta‐analysis was conducted utilizing Stata 12.0 statistical software. 26 studies involving 989 patients were included in the analysis. The recurrence rate in the laser combined with steroids therapy group (12.2%, 95% confidence interval [CI]: 5.9%–18.5%) was lower than that of the surgical excision combined with radiotherapy group (13.5%, 95% CI: 6.6%–22.2%). For the incidence of AEs, relatively low incidence of atrophy (0.0%, 95% CI: 0.0%–1.2%), telangiectasia (3.2%, 95% CI: 0.4%–7.6%), erythema (2.3%, 95% CI: 0.0%–10.6%), infection (0.2%, 95% CI: 0.0%–1.6%) and high hyperpigmentation rate (8.3%, 95% CI: 4.2%–13.4%) were obtained in the surgical excision combined with radiotherapy group. Compared with surgical resection followed by radiotherapy, the combination of laser and steroids for keloids showed a lower hyperpigmentation rate (6.5%), as well as a higher incidence of atrophy (22.7%), telangiectasia (6.4%), erythema (3.3%) and infection (3.3%). Only a hypopigmentation rate of 2.9% was obtained in patients treated with surgical excision plus radiotherapy. Current evidence revealed that surgical excision followed by adjuvant radiotherapy and laser combined with steroids therapy were effective and safe treatments for keloids, with relatively low recurrence rate and complication rate. Comparative studies are needed to further compare the effects of these two combination therapies on keloids.

1. INTRODUCTION

Keloid, a fibroproliferative disease, is the outcome of unwarranted fibroblast activity that typically follows scar development due to injury or surgical procedures. ¹ , ² These pathological formations, recognised by their pronounced red hue, tend to expand past the boundaries of the initial trauma site and are characteristically persistent, with rare instances of natural regression. ³ The aesthetic implications of these keloids can precipitate significant psychological distress, including diminished self‐esteem, heightened anxiety and depression. ⁴ Regrettably, the inherent resistance of keloids to spontaneous regression and their frequent refractoriness to therapeutic interventions pose considerable challenges. Contemporary treatment modalities encompass surgical approaches, intralesional and topical therapies, radiotherapy and laser‐based interventions. ⁵ , ⁶ , ⁷ Nevertheless, the optimal treatment strategy remains a subject of ongoing debate, complicating the clinical decision‐making process in the management of keloids. ⁸

The principal objective of therapeutic intervention should be to achieve a minimal rate of recurrence. While surgical removal of keloids is the primary treatment, it is related to a recurrence rate exceeding half of the cases. ² It has been observed that the recurrence rate in women undergoing adjuvant radiotherapy post‐surgery dropped to around 20%, in contrast to the 50% recurrence rate in patients who only had surgery. ⁹ Moreover, a comprehensive meta‐analysis of 9048 keloids across 72 studies indicated a lower recurrence rate in patients treated with adjuvant radiotherapy as opposed to those receiving radiotherapy alone. ¹⁰ Consequently, the combined approach of surgery resection and adjuvant radiotherapy currently represents a relatively superior treatment strategy for keloids. ¹¹ The application of laser technology in keloid treatment has been documented over several years. ¹² Laser therapy has gained popularity due to factors such as patient compliance, reduced discomfort and improved aesthetic outcomes. ¹³ However, when used independently, lasers have demonstrated limited efficacy in keloid management. ¹⁴ with recurrence rates paralleling those of traditional surgical excision alone, ranging from 45% to 100%. ¹⁵ The combination of various laser types with other treatment methods, including triamcinolone acetonide (TA), has led to encouraging success rates. Recent research has suggested that the combination of intralesional steroids with laser treatment enhanced efficacy and reduced recurrence rate. ¹⁵ , ¹⁶

Although multiple studies have reported the efficacy and safety of combined surgical excision with adjuvant radiotherapy and laser plus intralesional steroids in the treatment of keloids, the results vary across studies. Moreover, there is currently a lack of meta‐analysis comparing the treatment outcomes of these two combination therapies for keloids. Consequently, we performed a meta‐analysis to comprehensively estimate the recurrence rate and incidence of adverse events (AEs) after the combination of laser with steroids and surgery resection with adjuvant radiotherapy for keloids.

2. MATERIALS AND METHODS

2.1. Literature search

Two independent reviewers conducted a comprehensive search of the PubMed, Web of Science, Embase and Cochrane Library databases from inception to August 2023. A combination of subject headings and free‐text terms were used for literature retrieval. The adopted search terms included: ‘laser’, ‘triamcinolone’, ‘steroid’, ‘glucocorticoid’, ‘surgical excision’, ‘resection’, ‘radiotherapy’, ‘radiation’ and ‘keloid’. Additionally, the reference lists of relevant systematic reviews or meta‐analyses were reviewed to supplement the relevant literature. Details of the search terms are shown in the Supplemental Files 1.

2.2. Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) Study design: Prospective clinical trials, including randomised controlled trials (RCTs), nonrandomised controlled trials (N‐RCTs) and single‐arm clinical trials; (2) Study population: Patients with keloids undergoing laser and steroids, or surgical excision and radiotherapy; (3) Intervention: Laser combined with steroids as the intervention group, or surgical excision combined with radiotherapy as the intervention group; (4) Outcomes: Recurrence rate and incidence of AEs. The exclusion criteria were as follows: (1) Observational studies; (2) Duplicate publications; (3) Studies lacking available data; (4) Reviews, letters, case reports, conference abstracts.

2.3. Data extraction and quality assessment

Two researchers independently conducted the literature screening and data extraction, rigorously cross‐validating the criteria for inclusion and exclusion. In instances where consensus was elusive, a third researcher was brought into the discussion to facilitate agreement. The information collated from each study included: first author, publication year, study design, region, sex, sample size, age, treatment, follow‐up time and outcomes. The quality of noncomparative single‐arm clinical trials was evaluated using the methodological index for nonrandomised studies (MINORS) Methodological items. ¹⁷ The MINORS tool is composed of eight items for noncomparative studies, with additional four items for comparative studies. Each item was assigned a score: 0 (not reported), one (reported but inadequate), or two (reported and adequate). For the studies under review, a cumulative score of <8 points signified low quality, 8–12 points suggested intermediate quality and >12 points indicated high quality. The quality of RCTs was assessed using the modified Jadad scale, ¹⁸ which included randomization, concealment of randomization, double‐blinding and withdrawals and dropouts. A total score of 0–3 points indicated low quality and 4–7 points suggested high quality.

2.4. Statistical analysis

This meta‐analysis was conducted utilizing Stata 12.0 statistical software (StataCorp, College Station, TX, USA). Recurrence and AEs rates for each study were collected as a proportion of the specified population or the number of keloids and subsequently pooled binomial meta‐analyses were performed. To assess the heterogeneity of the pooled studies, we used the I ² test, which evaluated the premise that methodological variation across studies might influence the effect size. A random‐effects model was utilised to ascertain the pooled rate of recurrence or AEs and 95% confidence interval (CI). We conducted a sensitivity analysis to assess the reliability of the outcomes. Publication bias was evaluated by funnel plots and Egger's test. p Values <0.05 were considered statistically significant.

3. RESULTS

3.1. Study selection and quality assessment

The process of literature selection is shown in Figure 1. An initial search of databases revealed 7352 articles of relevance, which, after the removal of duplicates, were reduced to 5051. The subsequent review of titles and abstracts led to the exclusion of 4969 articles. After thoroughly reading the full text, 56 articles that were inconsistent with the research results were excluded, and ultimately 26 articles were included. ³ , ¹³ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² The basic characteristics of the included studies are detailed in Table 1. To obtain the latest pooled results, articles published since 1 January 2010 were merely included. An evaluation of the quality of included single‐arm clinical trials and RCTs is provided in the Supplemental Files 2.

FIGURE 1.

Flow diagram of the process of selection of articles.

TABLE 1.

Characteristics of eligible studies.

First author/year	Study design	Region	Sex (male/female)	Mean age (range)	Treatment	Follow‐up time	Outcomes
Wang 2020	Single‐arm clinical trial	China	20/21	6–62	CO2 laser + TA	24 Months	Recurrence rate, AEs
Garg 2011	Single‐arm clinical trial	India	19/9	16–60	CO2 laser + TA	12 Months	Recurrence rate, AEs
Tawaranurak 2022	RCT	Thailand	Group A: 5/6 Group B: 3/8	Group A: 44.8 ± 19.9 Group B: 42.6 ± 18.3	Group A: CO2 laser + TA; Group B: TA alone	12 Months	Recurrence rate, AEs
Behera 2016	RCT	India	Group A: 30 Group B: 30	≥12	Group A: CO2 laser + TA; Group B: Cryotherapy	12 Months	Recurrence rate, AEs
Vila Capel 2014	Single‐arm clinical trial	Spain	8/11	16–80	Surgical excision + radiotherapy	36 Months (mean)	Recurrence rate, AEs
Van Leeuwen 2014	Single‐arm clinical trial	The Netherlands	12/23	18–68	Surgical excision + radiotherapy	33.6 Months (mean)	Recurrence rate, AEs
Bhattacharya 2023	Single‐arm clinical trial	India	10/40	9–45	Surgical excision + radiotherapy	≥18 Months	Recurrence rate
Song 2014	Single‐arm clinical trial	Korea	2/10	20–60	Surgical excision + radiotherapy	20 Months (mean)	Recurrence rate, AEs
Mohammadi 2013	Single‐arm clinical trial	Iran	8/9	27.17 ± 7.10	Surgical resection + radiotherapy	16.35 Months (mean)	Recurrence rate, AEs
Liu 2018	Single‐arm clinical trial	China	35/10	16–36	Surgical resection + radiotherapy	18 Months (mean)	Recurrence rate, AEs
Lee 2015	Single‐arm clinical trial	Korea	7/23	11–66	Surgical resection + radiotherapy	27.4 Months (median)	Recurrence rate, AEs
Ha 2023	Single‐arm clinical trial	Korea	9/7	24–74	Surgical excision + radiation therapy	12 Months (mean)	Recurrence rate, AEs
Kim 2012	Single‐arm clinical trial	Korea	26 women	30–44	Surgical resection + radiotherapy	27 Months (median)	AEs
Khalid 2018	RCT	Pakistan	16/44	12–65	Group A: Intralesional 5‐FU + TA; Group B: Surgical resection + radiotherapy	6 Months	Recurrence rate
Jones 2019	Single‐arm clinical trial	USA	19/29	18–67	Surgical resection + radiotherapy	12 Months	Recurrence rate, AEs
Sreelesh 2023	N‐RCT	India	44/57	Group A: 31.58 (mean) Group B: 28.88 (mean)	Group A: Surgical excision + radiotherapy; Group B: Surgical excision + TA	12 Months	Recurrence rate, AEs
Jiang 2018	Single‐arm clinical trial	Germany	11/18	20–80	Surgical excision + brachytherapy	49.7 Months (median)	Recurrence rate, AEs
Jiang 2016	Single‐arm clinical trial	Germany	9/15	20–80	Surgical excision + radiation therapy	29.4 Months (median)	Recurrence rate, AEs
Hafkamp 2017	Single‐arm clinical trial	The Netherlands	12/12	15–64	Surgical excision + brachytherapy	53 Months (median)	Recurrence rate, AEs
Li 2022	RCT	China	18/37	18–70	Group A: Surgical excision + 5‐FU and betamethasone; Group B: 5‐FU and betamethasone; Group C: Surgical excision + radiotherapy	10 Months (median)	Recurrence rate, AEs
Emad 2010	N‐RCT	Iran	Group A: 19 Group B: 9	16–45	Group A: Surgical excision + radiotherapy; Group B: Cryotherapy + TA	19 Months (mean)	AEs
Aluko‐Olokun 2014	RCT	Nigeria	Group A: 30/24 Group B: 29/24	Group A: 27.4 (mean) Group B: 26.9 (mean)	Group A: TA; Group B: Surgical excision + radiotherapy	18 Months	Recurrence rate, AEs
Tresoldi 2021	Single‐arm clinical trial	Italy	6/10	19–59	Surgical excision + radiotherapy	6 Months	Recurrence rate, AEs
Son 2020	Single‐arm clinical trial	USA	8/7	22–65	Surgical excision + radiation therapy	6 Months	Recurrence rate
Kuribayashi 2011	Single‐arm clinical trial	Japan	5/16	18–69	Surgical excision + brachytherapy	18 Months (median)	Recurrence rate
Yamawaki 2011	Single‐arm clinical trial	Japan	27/33	10–80	Surgical excision + radiation therapy	38.3 Months (mean)	Recurrence rate

Abbreviations: 5‐FU, 5‐fluorouracil; AEs, adverse events; N‐RCT, nonrandomised controlled trials; RCT, randomised controlled trial; TA, triamcinolone acetonide.

3.2. Recurrence rate and AEs incidence

As shown in Table 2, for recurrence rate, the rate of the laser combined with steroids therapy group (recurrence rate: 12.2%, 95% CI: 5.9%–18.5%) was lower than that of the surgical excision plus radiotherapy group (recurrence rate: 13.5%, 95% CI: 6.6%–22.2%) (Figures 2 and 3). In terms of AEs, the rates of atrophy, telangiectasia, erythema and infection in the laser combined with steroids therapy group (atrophy: 22.7%, 95% CI: 1.1%–56.4%; telangiectasia: 6.4%, 95% CI: 0.1%–18.6%; erythema: 3.3%, 95% CI: 0.0%–19.2%; infection: 3.3%, 95% CI: 0.0%–11.0%) were higher than in the surgical excision plus radiotherapy group (atrophy: 0.0%, 95% CI: 0.0%–1.2%; telangiectasia: 3.2%, 95% CI: 0.4%–7.6%; erythema: 2.3%, 95% CI: 0.0%–10.6%; infection: 0.2%, 95% CI: 0.0%–1.6%), respectively. The incidence of hyperpigmentation was 6.5% (95% CI: 0.6%–16.3%) in the laser combined with steroids therapy group and 8.3% (95% CI: 4.2%–13.4%) in the surgical excision plus radiotherapy group. In addition, keloid patients treated with surgical excision plus radiotherapy had a hypopigmentation rate of 2.9% (95% CI: 0.4%–7.0%). However, there was a lacking hypopigmentation data of laser combined with steroids therapy for keloids (Figure S1‐2, Supplemental Files 3).

TABLE 2.

The rates of recurrence and adverse events after laser combined with steroids and surgical resection plus radiotherapy for keloids.

Groups and Outcomes	Included studies	Patients	Meta‐analysis			Heterogeneity
			Rate	95% CI	p	I 2 (%)	p
Laser combined with steroids
Recurrence rate	4	115	0.122	0.059–0.185	<0.001	0	0.859
Atrophy	3	86	0.227	0.011–0.564	0.020	84.772	0.001
Telangiectasia	4	110	0.064	0.001–0.186	0.035	64.772	0.036
Hyperpigmentation	2	53	0.065	0.006–0.163	0.010	0	‐
Erythema	3	82	0.033	0.000–0.192	0.316	75.794	0.016
Infection	4	144	0.033	0.000–0.110	0.074	59.003	0.062
Surgical excision combined with radiotherapy
Recurrence rate	20	805	0.135	0.066–0.222	<0.001	86.785	<0.001
Atrophy	5	160	0	0.000–0.012	1.000	0	0.996
Telangiectasia	10	317	0.032	0.004–0.076	0.005	56.307	0.015
Hyperpigmentation	14	466	0.083	0.042–0.134	<0.001	57.951	0.003
Hypopigmentation	7	218	0.029	0.004–0.070	0.006	31.011	0.191
Erythema	5	187	0.023	0.000–0.106	0.200	77.500	0.001
Infection	9	287	0.002	0.000–0.016	0.433	0	0.647

Abbreviation: CI, confidence interval.

FIGURE 2.

Forest plot of recurrence rate after laser combined with steroids for the treatment of keloids. CI, conidence interval.

FIGURE 3.

Forest plot of recurrence rate after surgical excision followed by adjuvant radiotherapy for keloids. CI, conidence interval; ES, effect size.

3.3. Sensitivity analysis and publication bias

Most of the included studies were single‐arm clinical trials, without comparative results. No results were ‘positive’ and there were no statistically significant outcomes, and all findings were stable. Consequently, we did not conduct any sensitivity analysis or publication bias tests. ⁴³

4. DISCUSSION

Keloids, recognised as pathologically hyperplastic scars, characteristically expand beyond the initial wound boundaries over time. ⁴⁴ These pathological scars predominantly manifest in high‐tension areas such as the scapula and back. The transformation of mechanical signals into chemical ones, facilitated by channels such as the TNF‐/NF‐B pathway, is thought to be tension‐induced. ⁴⁵ This tension may stimulate fibroblast proliferation, as well as the production and accumulation of collagen fibres, thereby contributing to pathological scar formation through the modulation of associated protein production. ⁴⁶ As a benign fibroproliferative disorder, the terminal development process is yet to be fully understood. Current therapeutic interventions primarily aim to suppress fibroblast proliferation, inhibit collagen deposition and mitigate inflammation. However, these treatments frequently result in relapses and fall short of providing a complete cure. Years of research indicate that monotherapy for keloids seldom leads to satisfactory outcomes. Recent clinical studies focusing on keloid treatment have demonstrated a preference for the implementation of combined therapy over monotherapy. ⁴⁷

Due to their abnormal appearance, inability to self‐resolve and associated discomfort such as pain and pruritus, keloids often necessitate surgical excision for patients seeking immediate relief. The surgical removal of keloids emerges as a potential therapeutic approach for mature keloids unresponsive to first‐line treatments. Nevertheless, when employed as a single treatment, it is related to a recurrence rate ranging from 45% to 100%. ⁴⁸ To mitigate the recurrence risk, the application of combined treatment has been pursued. The combination of surgical excision and subsequent radiotherapy has been demonstrated to be highly effective in minimizing recurrence. ⁷ Our meta‐analysis showed that the recurrence rate was only 13.5% after surgery excision combined with radiotherapy for keloids. A recent meta‐analysis revealed that surgical resection followed by adjuvant radiotherapy represented an effective treatment for keloids, with a recurrence rate of 22%. ⁴⁹ It may be that our pooled analysis included recently published studies since 2010, and therefore obtained relatively low recurrence rate. Radiation therapy functions by inhibiting fibroblast proliferation through the suppression of histamine release from mast cells and the release of transforming growth factor‐beta. ²⁷ Common complications include telangiectasia, erythema and hypo/hyperpigmentation. ⁵⁰ Relatively low incidences of telangiectasia, hyperpigmentation, hypopigmentation and erythema were obtained in our results, at 3.2%, 8.3%, 2.9% and 2.3%, respectively. In addition, the incidence of atrophy and infection was lower, with a rate of 0% and 0.2%. A systematic review indicated an overall complication rate of 19% for surgical excision followed by radiotherapy for keloids. ⁵¹ A recent review on adjuvant radiotherapy for keloids reported erythema as the most common acute complication, with a rate ranging from 1% to 100%, followed by infection (4.3%–8%). Chronic complications primarily encompass telangiectasia, with a rate of 4%–27% and skin colour changes (hypopigmentation 1.2%–100% or hyperpigmentation 0.3%–100%). ⁵² The variation in complication incidences reported in current and previous studies may be attributed to a multitude of factors, including patient's age, aetiology, lesion site, sensitivity, radiation delivery methods, dose and timing. ⁵¹

The therapeutic mechanism of laser treatment for keloids remains unclear, potentially involving local impairment to lesional blood vessels or direct inhibition of fibroblasts. While lasers have demonstrated efficacy as monotherapy for keloids, they are concurrently being explored in combining with other therapeutic agents to enhance drug delivery and penetration. ⁷ In present quantitative analysis, all of the four included studies were CO₂ laser combined with intralesional TA. Compared with surgical resection and adjuvant radiation therapy, the combination of CO₂ laser and intralesional TA treatment for keloids showed a lower recurrence (12.2%) and hyperpigmentation (6.5%) rates, as well as a higher incidence of atrophy (22.7%), telangiectasia (6.4%), erythema (3.3%) and infection (3.3%). Fractional CO₂ laser treatment engenders multiple diminutive perforations in the scar, instigating collagen remodelling and expediting scar repair, whilst preserving the epidermal integrity. ⁵³ The application of ablative laser‐assisted drug delivery augments drug penetration beyond the stratum corneum, bolstering the effect of topical steroids while minimizing tissue damage. Steroids possess the capacity to suppress inflammation, collagen and glycosaminoglycan synthesis and fibroblast proliferation, as well as to deter the denaturation of collagen and fibroblasts. ⁵⁴ , ⁵⁵ Steroids are the traditional keloid treatments and effectively enhance tissue flexibility, reduce thickness and alleviate pruritus and pain. ⁵⁶ The most commonly used steroids are TA. However, long‐term observation has revealed that 63% of patients experience local side effects, including hypopigmentation, telangiectasia and skin atrophy. ⁵⁷ Therefore, the higher incidence of complications after CO₂ combined with intralesional TA therapy for keloids may be attributed to the use of TA.

There was a lack of research evidence to directly compare the efficacy and safety of surgical excision followed by adjuvant radiotherapy with the combination of laser and intralesional steroids for keloids. It is still difficult to compare the recurrence rate and incidence of complications of these two combined therapies indirectly by quantitative synthesis. This is due to the heterogeneity of subject characteristics, including keloid size, number and location, skin tension, in addition to gender and Fitzpatrick skin type, all of which could influence keloid response. Furthermore, the limited number of participants, diverse schemes of laser combination therapy (for instance, varying doses and frequencies of TA injection) and quantitative synthesis of different treatment options (such as differing doses and timing of adjuvant radiotherapy), made it difficult to compare the results obtained. To our knowledge, this was the first systematic review to quantitatively report the recurrence rate and AE incidence after surgical resection combined with adjuvant radiotherapy and laser combined with steroids for keloids. Despite the lack of clinical comparative trials, it can still provide evidence‐based support for the future clinical management and selection of keloids.

Several limitations of this study should be considered. First, the recurrence and AEs rates in all included studies were not calculated in exactly the same way. Recurrence and AEs rates for each study were collected as a percentage for the given population or number of keloids, which may lead to potential heterogeneity. Second, the dose and frequency of intralesional TA injection, or the dose and timing of adjuvant radiotherapy adopted by the same combination treatments were not consistent across the included studies. Third, only four studies were included in the laser combination group, making the pooled results unconvincing. Further studies are needed to verify the results.

5. CONCLUSION

In summary, the present meta‐analysis suggested that surgical excision followed by adjuvant radiotherapy and laser combined with steroids therapy were effective and safe treatments for keloids, with relatively low recurrence rate and complication rate. The recurrence and hyperpigmentation rates of keloids treated with laser combined with steroids were lower than those of surgical excision combined with radiotherapy. While the incidence of atrophy, telangiectasia, erythema and infection in keloids treated with surgical resection followed by radiation therapy was lower than that of laser combined with steroids therapy. Comparative studies are needed to further compare the effects of these two combination therapies on keloids.

CONFLICT OF INTEREST STATEMENT

The authors declare that there is no conflict of interest.

Supporting information

Data S1. Supporting information.

Fu S, Duan L, Zhong Y, Zeng Y. Comparison of surgical excision followed by adjuvant radiotherapy and laser combined with steroids for the treatment of keloids: A systematic review and meta‐analysis. Int Wound J. 2024;21(3):e14449. doi: 10.1111/iwj.14449

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.