Levels of evidence for the treatment of keloid disease☆☆☆

Article Outline

• Summary
• Methods
• Results (see Table 2)
• Silicone-based therapy
• Intralesional steroids
• Cryosurgery
• 5-Fluorouracil
• Interferon
• Lasers
• Surgery and adjuvant therapy
  • Steroids
  • Mitomycin C
  • Verapamil
  • Interferon
  • 5-Fluorouracil
  • Imiquimod
  • Pressure
  • Radiotherapy
  • Combination adjuvant therapy
• Other therapy
• Discussion
• References
• Copyright

Summary 

Introduction

Keloid disease presents a significant burden for patients and a significant therapeutic challenge for clinicians. Multiple treatments have been proposed, but with the increasing drive towards effective use of resources, therapeutic options need to be evaluated in terms of the levels of evidence supporting their use.

Aim

To retrieve and review the primary clinical studies evaluating keloid disease therapy over the last 25 years and assign levels of evidence for the treatment modalities evaluated.

Method

A Medline search was conducted to identify all primary clinical studies evaluating the treatment of keloid disease, published in English since 1980 (excluding single case reports). Studies were assigned a level of evidence (LOE-1, highest quality to LOE-5, lowest) adapted from the Oxford Centre for Evidence-based Medicine.

Results

13 (12%) of 112 studies retrieved were assigned LOE-2, 99 (88%) assigned LOE-4. There were no LOE-1 studies. Ten of the LOE-2 studies evaluated silicone-based therapy or laser therapy. Most studies evaluating steroids, cryosurgery, laser therapy and post-surgical adjuvant therapy provide level 4 evidence.

Conclusion

High quality research in evaluating keloid therapy is lacking. There is a definite need for well designed and properly reported randomised controlled trials, to provide clinicians with a sound body of evidence on which to inform decision making.

Keywords: Levels of evidence, Keloid disease, Keloid scarring, Management, Therapy, Prevention

There has been a consistent drive for the effective use of health resources and a shift in emphasis toward evidence-based research in health care to enhance quality, safety and efficacy. In the UK, The National Institute for Clinical Excellence has been set up to appraise the available evidence for therapeutic interventions and provide national guidelines for the management of certain diseases and conditions.¹ The available evidence can be classified using a hierarchy ranging from the strongest (level 1) to the weakest evidence (level 5); this is then used to apply grades of recommendation for the therapeutic options to reflect the quality of the evidence supporting their use.

Keloid disease presents a healthcare challenge. Keloid scars often result from an abnormal tissue response to dermal injury, although cases of spontaneous keloids have been reported. These scars are raised and spread beyond the margins of the original wound, invading the surrounding normal skin in a site-specific way,² in contrast to hypertrophic scars, which are the result of an exaggerated wound healing response and stay confined to the boundaries of the original lesion. Histologically, keloids have a swirling nodular pattern of collagen fibres³ and the resulting fibrous growths invading normal dermis can produce masses in subcutaneous tissue.⁴ These fibrous growths can cause significant disfigurement and unwanted symptoms such as pruritus and pain.⁵ The inflammation, pruritus, and pain can be especially severe during the growth phase, but even long-standing lesions may continue to have tender and painful margins.⁴

The management of keloid disease has remained a difficult challenge for clinicians and multiple treatments have been advocated, with varying degrees of success, including established therapies (surgery, steroids, radiation, lasers, silicone gel sheets), as well as more experimental therapies such as interferon, 5-fluorouracil and retinoic acid. An International Advisory Panel on scar management⁶ developed consensus guidelines that recommended a combination of silicone gel sheeting and intralesional corticosteroids as first-line therapy, with the use of localised pressure therapy if possible (e.g. for earlobe keloids). Second-line therapy for resistant cases includes specific wavelength laser therapy and then surgery with adjunctive silicone gel sheeting, if required. Combination and monotherapy using more experimental methods should be conducted in units specialising in scar therapy.

Recurrence rates have been reported for many of these techniques: for example, 33% at 1 year with intralesional steroids alone⁷; 7%⁸ and 8%⁸⁶ using excision and adjunctive intralesional steroids; and in excess of 50% for CO₂ laser therapy.⁷⁸

Although the therapeutic options have been critically reviewed in the literature⁵, ⁶, ⁹, ¹⁰, ¹¹, ¹² and guidelines developed,⁶ the information has not been assessed with application of the levels of evidence for each treatment modality. In addition, many papers generalise treatments that have been studied in hypertrophic scars and apply these to keloid scarring, despite evidence showing that differences between the two entities exist, and that each responds differently to treatment.¹⁰

The aim of this study is to retrieve the primary clinical studies evaluating keloid disease therapy over the last 25 years and assign levels of evidence for the treatment modalities evaluated.

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Methods 

A Medline (www.pubmed.com) search was conducted to identify all relevant clinical studies evaluating the treatment of keloid disease, published in English since 1980. Keywords used in the search in various combinations included the following (* used as wildcard truncation): keloid*, treat*, therap*, manag*, surg*, excis*, triamcinolone, steroid, corticosteroid, cryosurgery, cryotherapy, fluorouracil, 5-FU, IFN, interferon, laser, silicon, SGS, radiation and radiotherapy. The search excluded single case reports, letters, animal or in vitro studies, studies evaluating prophylactic treatment, and studies evaluating hypertrophic scars only. Review articles were used as additional sources of primary papers by cross-checking the reference sections with the master list of compiled articles. The cross-referencing process of locating other studies was continued until no further articles were generated.

The articles were grouped by the primary treatment strategy being evaluated and article abstracts were then assessed and assigned a level of evidence (LOE) adapted from the Oxford Centre for Evidence-based Medicine¹³ (http://www.cebm.net/levels_of_evidence. asp). These levels, ranging from LOE-1 to LOE-5, are based on methodology and study design (see Table 1). Full text articles were retrieved for those studies in which the abstract did not provide enough information for assigning a level of evidence or for those studies which required further assessment of methodological quality.

Table 1. Levels of Evidence (Adapted from Oxford Centre of Evidence Based Medicine¹³

The quality of comparative studies was evaluated in terms of clear definition of comparison groups, standardised and blinded assessment of outcomes in both groups, sample size (>50 cases) and length of follow up (at least 1 year for assessing keloid recurrence),¹⁰ as well as randomisation technique, allocation concealment and blinding technique for randomised controlled trials (RCTs). Studies lacking in any of these attributes were downgraded (LOE-1 to 2 for RCTs and LOE-2 to LOE-4 for non-randomised comparative/cohort studies). Each study was also assessed for the direction of the conclusions, whether positive, negative or inconclusive for the treatment evaluated. For comparative studies, the treatment concluded to be more effective was recorded.

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Results (see Table 2) 

From a total of 112 primary studies retrieved using our search strategy, 13 (12%) were RCTs, but all assigned LOE-2 because of low quality (one study¹⁸ described more than one phase, and the two phases were reviewed as separate studies). Twelve non-randomised comparative studies were retrieved but all were assigned a lower level of evidence (LOE-4) because of methodological quality. Eighty-six (77%) studies were case series with no comparative group, also providing LOE-4 evidence. One case control study (LOE-3) was retrieved, but downgraded to LOE-4 and single case reports (LOE-5) were excluded from the search strategy. Therefore, overall, 99/112 (88%) studies provided level 4 evidence and 13/112 (12%) provided level 2 evidence for the treatment modality evaluated.

Table 2. Studies with assigned Levels of Evidence

Author	LOE	Study design	Treatment evaluated	Outcome
Silicone-based therapy (Monotherapy)
Gold18 (phase I)	2	Low quality RCT	SGS vs untreated control	+ SGS
De Oliveira19	2	Low quality RCT	SGS vs untreated control; SGS vs non-silicone gel sheet	NS
Berman20	2	Low quality RCT	Silicone cushion vs SGS	NS
Sawada14	2	Low quality RCT	Silicone cream with adherent film vs silicone cream with light dressing	+ silicone/film
Palmieri15	2	Low quality RCT	Silicone plates with vitamin E vs SGS	+ silicone plates vit E
Boutli-Kasapidou40	4	Low quality non-randomised comparative study	Cryo/steroids/SGS vs SGS	+ cryo/steroid/SGS
Paquet68	4	Low quality non-randomised comparative study	PDL vs SGS	NS
Fulton21	4	Case-series	SGS	+
Gold22	4	Case-series	SGS	+
Dockery23	4	Case-series	SGS	+
Mercer24	4	Case-series	SGS	+
Quinn25	4	Case-series	SGS	+
Ohmori26	4	Case-series	SGS	+
Chuangsuwanich27	4	Case-series	SGS	+
Hirshowitz28	4	Case-series	Silicone cushion	+
Wong29	4	Case-series	Silicone cream with dressing	+
Katz30	4	Case-series	SGS	+
Total Studies: 17	LOE-1: 0	LOE-2: 5	LOE-3: 0	LOE-4: 12
Intralesional steroids (Mono-and combination therapy)
Darzi36	2	Low quality RCT	Beta radiation vs steroid	+ Steroid
Layton37	2	Low quality RCT	Cryo vs steroid	NS
Manuskiatti39	2	Low quality RCT	Steroid vs 5-FU vs steroid/5FU vs PDL	NS
Yosipovitch38	4	Low quality non-randomised comparative study	Cryo/steroid vs cryosurgery vs steroid	+ Cryo/steroid
Boutli-Kasapidou40	4	Low quality non-randomised comparative study	Cryo/steroid/SGS vs SGS	+ Cryo/steroid/SGS
Muneuchi41	4	Case-series	Steroid	−
Lahiri42	4	Case-series	Steroid/cryo	+
Hirshowitz43	4	Case-series	Steroid/cryo	+
Russell44	4	Case-series	Steroid/pressure	+
Connell45	4	Case-series	Steroid/PDL	+
Fitzpatrick46	4	Case-series	Steroid/5FU/PDL	+
Yencha47	4	Case-series	Steroid/pressure/CO2 laser	+
Total Studies: 12	LOE-1: 0	LOE-2: 3	LOE-3: 0	LOE-4: 9
Cryosurgery (Monotherapy)
Layton37	2	Low quality RCT	Cryo vs. Steroid	NS
Yosipovitch38	4	Low quality non-randomised comparative study	Cryo vs Cryo/steroid vs Steroid	+ Cryo/steroid
Har-Shai48	4	Case-series	Cryo	+
Shepherd49	4	Case-series	Cryo	−
Muti50	4	Case-series	Cryo	+
Rusciani51	4	Case-series	Cryo	+
Zouboulis52	4	Case-series	Cryo	+
Gupta53	4	Case-series	Cryo	+
Fikrle54	4	Case-series	Cryo	+
Total Studies: 9	LOE-1: 0	LOE-2: 1	LOE-3: 0	LOE-4: 8
Laser therapy (Mono- and combination therapy)
Manuskiatti39	2	Low quality RCT	Steroid vs 5-FU vs steroid/5FU vs PDL	NS
Alster67	4	Low quality non-randomised comparative study	PDL vs untreated control	+ PDL
Paquet68	4	Low quality non-randomised comparative study	PDL vs SGS	NS
Gold 18 (phase II)	4	Low quality non-randomised comparative study	CO2 laser/SGS vs CO2 laser	+ CO2 laser/SGS
Dierickx69	4	Case-series	PDL	+
Connell45	4	Case-series	PDL/steroid	+
Fitzpatrick46	4	Case-series	PDL/steroid/5FU	+
Abergel70	4	Case-series	Nd:YAG	+
Sherman71	4	Case-series	Nd:YAG	+
Kumar72	4	Case-series	Nd:YAG	+
Henderson73	4	Case-series	CO2 laser	+
Kantor74	4	Case-series	CO2 laser	+
Stucker75	4	Case-series	CO2 laser+− steroids	+
Conejo-Mir66	4	Case-series	CO2 laser/IFN-α2b	+
Apfelberg76	4	Case-series	CO2 laser	−
Stern77	4	Case-series	CO2 laser	−
Norris78	4	Case-series	CO2 laser	−
Yencha47	4	Case-series	CO2 laser/steroid/pressure	+
Hulsbergen79	4	Case-series	Argon laser	−
Apfelberg80	4	Case-series	Argon/CO2 laser	−
Total Studies: 20	LOE-1: 0	LOE-2: 1	LOE-3: 0	LOE-4: 19
5-Fluorouracil (Monotherapy)
Manuskiatti39	2	Low quality RCT	Steroid vs 5-FU vs steroid/5FU vs PDL	+
Gupta57	4	Case-series	5-FU	+
Nanda58	4	Case-series	5-FU	+
Apikian59	4	Case-series	5-FU	+
Kontochristopoulos60	4	Case-series	5-FU	+
Total Studies: 5	LOE-1: 0	LOE-2: 1	LOE-3: 0	LOE-4: 4
Interferon (Monotherapy)
Granstein63	4	Low quality non-randomised comparative study	IFN-γ vs Placebo	+ IFN-γ
Al-Khawajah64	4	Low quality non-randomised comparative study	IFN-α2b vs Placebo	NS
Larrabee65	4	Case-series	IFN-γ	+
Total Studies: 3	LOE-1: 0	LOE-2: 0	LOE-3: 0	LOE-4: 3
Other therapy
Phillips136	2	Low quality RCT	Hydrocolloid dressing vs moisturiser	NS
Sawada16	4	Low quality non-randomised comparative study	Non-silicone cream with adherent film vs Vaseline	+ Non-silicone cream with adherent film
Malaker130	4	Case-series	Primary radiotherapy	+
Espana131	4	Case-series	Bleomycin	+
Saray132	4	Case-series	Bleomycin	+
Janssen de Limpens133	4	Case-series	Retinoic acid	+
Panabiere-Castaings134	4	Case-series	Retinoic acid)	+
Soderberg135	4	Case-series	Adhesive zinc tape	+
Total Studies: 8	LOE-1: 0	LOE-2: 1	LOE-3: 0	LOE-4: 7
Surgery and adjuvant therapy
Surgery alone
Sclafani101	2	Low quality RCT	Excision alone vs post-excn RXT vs post-excn steroid	NS
Berman95	4	Low quality non-randomised comparative study	Excn alone vs post-excn IFN-α2b vs post-excn steroid	+ Post-excn IFN-α2b
Lee81	4	Case-series (core excision)	Core excn alone	+
+ Steroids
Sclafani101	2	Low quality RCT	Post-excn steroid vs excn alone vs post-excn RXT	NS
Berman95	4	Low quality non-randomised comparative study	Post-excn steroid vs excn alone vs post-excn IFNα2b	+ Post-excn IFN-α2b
Martin-Garcia98	4	Low quality non-randomised comparative study	Post-excn steroid vs post-excn imiquimod	+ Post-excn imiquimod 5%
Lawrence82	4	Low quality non-randomised comparative study	Post-excn steroid vs post-excn oral colchinine	NS
Lindsey127	4	Low quality non-randomised comparative study	Post-excn steroid vs post-excn steroid/RXT vs post-excn steroid/silicone	+ Post-excn steroid/RXT or steroid/silicone
Shons83	4	Case-series	Post-excn steroid	+
Golladay84	4	Case-series	Post-excn steroid	+
Tang85	4	Case-series	Post-excn steroid	+
Chowdri86	4	Case-series	Post-excn steroid	+
+ Mitomycin C
Talmi87	4	Case-series	Post-excn mitomycin C	+
Sanders88	4	Case-series	Post-excn mitomycin C	−
+ Verapamil
D'Andrea92	4	Low quality case-control study	Post-excn verapamil/SGS vs post-excn SGS	+ Post-excn verapamil/SGS
Copcu89	4	Case-series	Post-excn verapamil	+
Lawrence91	4	Case-series	Post-excn verapamil/pressure	+
+ Interferon
Broker93	2	Low quality RCT	Post-excn IFN-γ vs post-excn saline	− Post-excn IFN-γ
Davison94	2	Low quality RCT	Post-excn IFN-α2b vs post-excn steroid	− Post-excn IFN-α2b
Berman95	4	Low quality non-randomised comparative study	Post-excn IFN-α2b vs post-excn steroid vs excn only	+ Post-excn IFN-α2b
+ 5-Fluorouracil
Uppal96	2	Low quality RCT	Post-excn 5FU vs post-excn saline	+ Post-excn 5FU
+ Imiquimod
Martin-Garcia98	4	Low quality non-randomised comparative study	Post-excn imiquimod vs post-excn steroid	+ Post-excn imiquimod 5%
Berman97	4	Case-series	Post-excn imiquimod	+
+ Pressure
Rauscher100	4	Case-series	Post-excn pressure	+
+ Radiotherapy (irradiation doses in Gray, Gy)
Sclafani101	2	Low quality RCT	Post-excn RXT vs post-excn steroid vs excn alone	NS
Darzi36	2	Low quality RCT	Pre-and post-excn RXT vs post-excn RXT	NS
Ollstein102	4	Case-series	Post-excn RXT (15Gy)	+
Enhamre103	4	Case-series	Post-excn RXT (10–15Gy)	+
Borok104	4	Case-series	Post-excn RXT (4–12Gy)	+
Kovalic105	4	Case-series	Post-excn RXT (3–20Gy)	+
Sallstrom106	4	Case-series	Post-excn RXT (18Gy)	+
Doornbos107	4	Case-series	Post-excn RXT (9–16Gy)	+
Chen108	4	Case-series	Post-excn RXT (15–21Gy)	+
Supe109	4	Case-series	Post-excn RXT (20Gy)	+
Ship110	4	Case-series	Post-excn RXT (15Gy)	+
Escarmant111	4	Case-series	Post-excn RXT (8–30Gy)	+
Klumpar112	4	Case-series	Post-excn RXT (3.2–16Gy)	+
Chaudhry113	4	Case-series	Post-excn RXT (18Gy)	+
Durosinmi-Etti114	4	Case-series	Post-excn RXT (5–15Gy)	+
Norris115	4	Case-series	Post-excn RXT (8–12Gy)	+
Clavere116	4	Case-series	Post-excn RXT (12–15Gy)	+
Wagner117	4	Case-series	Post-excn RXT (7.5–28Gy)	+
Guix118	4	Case-series	Post-excn RXT (12Gy)	+
Ragoowansi119	4	Case-series	Post-excn RXT (10Gy)	+
Caccialanza120	4	Case-series	Post-excn RXT (15–40Gy)	+
Maarouf 121	4	Case-series	Post-excn RXT (5–18Gy)	+
Ragoowansi122	4	Case-series	Post-excn RXT (10Gy)	+
Ogawa123	4	Case-series	Post-excn RXT (15Gy)	+
Garg124	4	Case-series	Post-excn RXT (15Gy)	+
Malaker125	4	Case-series	Post-excn RXT (16Gy)	+
Fraunholz126	4	Case-series	Post-excn RXT (20Gy)	+
+ Combination adjuvant therapy
D'Andrea92	4	Low quality case-control study	Post-excn verapamil/SGS vs post-excn SGS	+ post-excn verapamil/SGS
Lindsey127	4	Low quality non-randomised comparative study	Post-excn steroid/RXT vs post-excn steroid/silicone vs post-excn steroid	+ steroid/RXT or steroid/silicone
Lawrence91	4	Case-series	Post-excn verapamil/pressure	+
Rauscher100	4	Case-series	Post-excn steroid tape/pressure	+
Agrawal128	4	Case-series	Post-excn steroid/pressure	+
Akoz129	4	Case-series	Post-excn steroid/silicone	+
Total Studies: 48	LOE-1: 0	LOE-2: 5	LOE-3: 0	LOE-4: 43

Abbreviations: NS, no significant difference; +, positive; −, negative; SGS, silicone gel sheet; PDL, pulsed-dye laser; Excn, excision; RXT, radiotherapy.

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Silicone-based therapy 

Silicone has been used in various forms including silicone cream,¹⁴ silicone oil or gel with additives such as vitamin E¹⁵ and silicone gel either topically or as adhesive sheets. Silicone gel sheeting is soft, self-adhesive and semi-occlusive, made from medical grade silicon (cross-linked polymer of dimethethylsiloxane) and reinforced with a silicon membrane backing. The mechanism of action is unclear, although it has been postulated that it acts as an impermeable membrane that keeps the skin hydrated.¹⁶, ¹⁷ Use of silicone gel sheets requires patient compliance, since it has been recommended that the sheet covers the entire scar for periods of at least 12h each day, and ideally 24h.¹²

Two RCTs¹⁸, ¹⁹ compared silicone gel sheeting (SGS) with no treatment. In phase I of a study, Gold¹⁸ applied silicone gel sheeting to hypertrophic and keloid scars in 21 patients; scars were divided into two equal areas, with one half randomly allocated to receive no treatment, and the other received SGS for a minimum of 12h a day, for 12 weeks. Both patients and clinicians assessed changes in scar thickness and colour using non-validated measures and assessed ‘overall effectiveness’. Outcomes were reported as better for the SGS group, compared to control, although randomisation technique and blinding was not reported, and follow up was only 12 weeks.

De Olivera et al.¹⁹ conducted a RCT in 26 patients (41 hypertrophic and keloid scars); in patients with two scars, one received SGS, the other a non-silicone gel sheet, both applied for 24h a day; in patients with three scars, the third scar was used as a control with ‘no treatment’. Non-validated clinical assessments of scar dimensions (length, width), colour, and induration were used, in addition to a measure of the intracicatrical pressure and patient assessment of relief of pruritus and pain. The study found no significant difference between SGS and control or SGS and non-silicone gel sheets, although no randomisation technique was reported, analysis was combined for keloid and hypertrophic scarring and follow up was less than 6 months.

In a small RCT,²⁰ 22 patients with keloid scars were randomly assigned to use silicone gel cushion or silicone gel sheeting. Clinical assessments of scar dimensions, volume, colour and induration and patient assessment of symptoms were made at baseline and after 16 weeks of treatment. No statistically significant differences in outcome measures were found between the two therapies. In another study¹⁵ in which hypertrophic and keloid scars were analysed together, 80 patients were randomised to treatment with silicone plates with vitamin E or SGS alone, both applied for 10h overnight. Using a non-validated assessment of scar appearance and a symptom scale for pruritus and pain, the authors report significantly better outcomes in those treated using silicone plates with vitamin E. However, follow up was limited to 4 and 8 weeks and no method of randomisation was reported. Sawada et al.¹⁴ found that silicone cream used with plastic adherent film was more effective than silicone cream with light dressing alone, however the sample of four keloid scars was very small and randomisation technique and blinded assessment of outcomes was not reported. In a non-randomised controlled trial, the same group¹⁶ found that non-silicone cream with plastic adherent film was superior to control (Vaseline cream), implying that the efficacy of silicone gel sheets is based on hydration and occlusion rather than the inherent properties of silicone. Again, however, the study suffered from small sample size, short-term follow up and non-blinded outcome assessment.

The remaining studies were case series,²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰ providing level 4 evidence and concluding positively in favour of the evaluated silicone-based therapy, the majority based on silicone gel sheeting. An extensive Cochrane review³¹ evaluating the evidence for silicone gel sheets concluded that any effects were obscured by the poor quality of research.

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Intralesional steroids 

A range of steroid preparations can be used for intralesional injection, including hydrocortisone acetate, methylprednisone (Depomedrol), dexamethasone and triamcinolone acetate, with the latter being the most commonly used.⁹ Proposed mechanisms of action include inhibition of collagen synthesis,³² inhibition of keloid fibroblast growth,³³ fibroblast degeneration,³⁴ and downregulation of collagen gene expression in keloids.³⁵

In a randomised study,³⁶ 65 patients with 100 lesions (58 keloid scars, KS) were assigned to four treatment arms of beta radiation alone (11 KS), intralesional steroids alone (17 KS), excision with pre- and postoperative radiation (15 KS) or excision with postoperative radiation only (15 KS). The first two groups were compared according to symptomatic success and reduction in scar thickness, and the latter two groups according to recurrence. In the steroid group, the total dose of triamcinolone acetonide was given with four injections at 1–2 week intervals, and was dependent on lesion surface area (1–2cm²: 20–40mg per course; 2–6cm²: 40–80mg; 6–12cm²: 80–120mg; with courses repeated if necessary). Full flattening was significantly more frequent in the intralesional steroid group, compared to beta radiation alone (400cGy twice a week to a total of 16Gy per course). Intralesional steroids also resulted in symptomatic relief in a greater number of keloids compared to beta radiation, however statistical significance was not reported. Although a simple randomisation technique was used, allocation blinding was not reported and there was no report of the methods used to measure outcomes or whether assessment was standardised and blinded. In addition, the sample size was small and recurrence was not assessed for the steroid and radiation groups.

In another RCT³⁷ with short-term follow up (8 weeks), Layton et al. concluded that intralesional triamcinolone therapy (total 5mg per keloid) was not as effective as cryotherapy, in terms of lesion flattening, for early, vascular lesions (assessed by laser Doppler flow). However, definitive analysis was difficult because of the sample size (n=11 patients).

The use of intralesional steroids in combination with other therapy has also been evaluated. Triamcinolone acetate treatment (40mg/ml, 0.1ml per cm²) combined with cryosurgery, was found to be more effective than steroid treatment or cryosurgery alone, in a non-randomised comparative trial³⁸ although sample size was small, not all assessments were blinded and recurrence was only assessed up to 8 months post-therapy. In a RCT³⁹ no significant differences in scar height or erythema were found between groups treated with intralesional triamcinolone alone (20mg/ml every 4 weeks for a total of six treatments), 5-fluourouracil alone (50mg/ml for a total of 10 treatments over 24 weeks) or triamcinolone and 5-FU combined (triamcinolone 1mg/ml mixed with 5-FU 45mg/ml for a total of 10 treatments over 24 weeks); the study also suffered from a small sample size, limited follow up of 32 weeks and no report of the randomisation technique, or whether assessments of outcome were blinded.

The combination of intralesional triamcinolone acetonide (0.1%, 10–40mg/ml, once monthly for 3 months), local silicone gel (three times daily for 12 months) and cryosurgery was found to be more effective than the control treatment of silicone sheets alone (applied 20h daily for 1 year), in a non-randomised, non-blinded comparative study,⁴⁰ but the control arm consisted of both keloid and hypertrophic scars.

One case series study⁴¹ provides negative level 4 evidence for the use of intralesional steroids as monotherapy; 109 keloid scars were treated in 94 Asian patients using 1–10mg of intralesional triamcinolone acetonide, diluted using 1% lignocaine, per scar at each treatment, with minimum 4-weekly intervals between injections. A non-validated clinical score including ‘redness’ and ‘prominence’ and ‘patient reported relief of symptoms’ were used to assess success of the treatment. Although symptoms improved in 52 patients (55%), excellent or good clinical scores were only obtained in 25 patients (26%); the authors partially attributed this to the lower doses of steroid used and longer treatment intervals. Other LOE-4 studies report positively in favour of the use of intralesional steroids in combination with cryosurgery,⁴², ⁴³ pressure therapy,⁴⁴ pulsed-dye laser,⁴⁵ pulsed-dye laser with 5-FU⁴⁶ and CO₂ laser with pressure therapy.⁴⁷ The use of steroids as post-excision adjuvant therapy is discussed later.

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Cryosurgery 

Ischaemic damage induced by the freeze/thaw cycle leads to cellular anoxia, with subsequent tissue necrosis⁹ and should lead to a reduction in keloid size. Scars treated with cryosurgery have also been shown to have a more organised architecture of collagen fibres.⁴⁸

Layton et al.³⁷ conducted a small RCT (n=11, described above) comparing intralesional steroids with cryosurgery, and used assessments of palpability, diameter, ultrasound depth and laser Doppler flow to evaluate outcomes at 8 weeks. Cryosurgery was found to be more effective in lesions with greater vascularity, and for both treatments lesions on the back responded better than on the chest. One case series of 17 patients⁴⁹ provides negative level 4 evidence for the use of cryosurgery as monotherapy, with only two scars attaining complete flattening. The remaining six LOE-4 studies provide positive evidence in favour of its use⁴⁸, ⁵⁰, ⁵¹, ⁵², ⁵³, ⁵⁴ (n ranging from four to 55 patients).

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5-Fluorouracil 

5-Fluorouracil (5-FU) is a pyrimidine analogue used mainly as a chemotherapeutic agent. Studies have demonstrated that 5-FU can inhibit fibroblast proliferation both in vitro and in vivo⁵⁵, ⁵⁶ and this has formed the basis of its experimental use in keloids. An LOE-2 study³⁹ found that intralesional 5-FU was as effective as treatment with steroids alone, pulse-dyed laser alone or steroids combined with 5-FU. The use of 5-FU with laser and steroids was reported favourably by an LOE-4 study.⁴⁶ The remaining four studies provided positive level 4 evidence for the use of 5-FU as monotherapy.⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰

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Interferon 

Both alpha and gamma interferons have demonstrated potent inhibition of fibroblast collagen synthesis⁶¹ and keloid treatment with interferon-alpha2b resulted in normalisation of keloid fibroblast collagen, glycosaminoglycan and collagenase production in vitro.⁶²

Two controlled comparative studies⁶³, ⁶⁴ evaluated the use of intralesional interferon compared to placebo; interferon-gamma was found to be effective,⁶³ but interferon alpha-2b ineffective,⁶⁴ in height reduction, compared to controls. However, both studies had small sample sizes (n=10 and 13 patients, respectively) and less than 1 month follow up. LOE-4 studies reported successful treatment with interferon-gamma as monotherapy⁶⁵ and interferon-alpha2b in combination with CO₂ laser ablation.⁶⁶

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Lasers 

Lasers cause a thermal tissue reaction that is tissue-specific depending on the wavelength applied. The lasers most commonly used in studies of keloid therapy are the CO₂ laser (wavelength 10 600nm), argon laser (488nm), neodymium:yttrium-aluminum-garnet (Nd:YAG, 1064nm) and the flashlamp pumped pulsed dye laser (585nm).

The pulsed-dye laser (PDL) has been evaluated in two non-randomised comparative studies⁶⁷, ⁶⁸; Alster et al.⁶⁷ conducted blinded assessments of scars treated with 585nm PDL, with an untreated half of the scar serving as control, and found greater reduction of pruritus and erythema in the PDL-treated group. The sample size was small and no distinction was made between keloid and hypertrophic scars for the purposes of analysis. Follow up was limited to 6 months. Paquet et al.⁶⁸ conducted a non-randomised controlled trial and found no significant differences between PDL-treated and silicone gel sheet-treated groups, with regards to scar erythema. However, follow up was short, no information was provided regarding the control group and blinding of assessments was not reported.

Case series studies have provided positive evidence in favour of PDL,⁶⁹ Nd:YAG laser⁷⁰, ⁷¹, ⁷² and the CO₂ laser.⁷³, ⁷⁴

Stucker et al.⁷⁵ describe a series using CO₂ laser excision, with wounds left open to heal by secondary intention; results were positive when combined with intralesional steroids for early recurrences. In phase II of his study, Gold¹⁸ excised two keloids using the CO₂ laser on each of eight patients; after laser excision, one scar was covered with SGS (minimum 12h/day for 12 weeks) and the other scar left untreated; recurrence rates of 1/8 in the SGS group, and 3/8 in the control group were reported. The remaining case series were negative for CO₂⁷⁶, ⁷⁷, ⁷⁸, ⁸⁰ and argon lasers.⁷⁹, ⁸⁰

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Surgery and adjuvant therapy 

Historically, surgical excision of keloids alone has been associated with high recurrence rates,⁶, ¹⁰ but one LOE-4 study⁸¹ favourably describes the use of a novel keloid core excision technique in 24 keloids of the ear, trunk, face and genitalia, without the need for adjunctive therapy. The other studies evaluate adjuvant steroid, mitomycin C, verapamil, interferon, 5-fluorouracil, imiquimod, pressure and radiotherapy.

Steroids 

A non-randomised comparative trial⁸² evaluated 27 keloids in 16 patients treated with surgery and adjunctive triamcinolone (two preoperative does of 120mg, and three postoperative doses of 40mg) and 28 keloids in 20 patients treated with surgery and oral colchinine (1.2mg daily, commenced 3 weeks after surgery for 5 months). There was no significant difference between the two groups in terms of recurrence (70% vs 68%, respectively); however those who did not have 1 year follow up were excluded from the analysis. The remaining four LOE-4 studies provide positive evidence favouring postoperative steroid therapy.⁸³, ⁸⁴, ⁸⁵, ⁸⁶ Shons et al.⁸³ evaluated 31 earlobe keloids in 20 patients, after surgical excision and adjunctive therapy using three postoperative injections of triamcinolone (0.1–0.2ml of 40mg/ml, 4 week intervals, commencing 3 weeks postoperatively). In a follow-up period of 12 to 62 months, only one keloid recurred. A series⁸⁴ of 19 patients with 28 keloid scars also reported only one recurrence, at 15 months follow up; betamethasone sodium and betamethasone acetate suspension was injected at the time of surgery only, but the dose not stated. Tang et al.⁸⁵ described a series of 11 patients with eight keloid scars, injected intraoperatively and weekly postoperatively with triamcinolone (10–30mg/ml). Postoperative follow up ranged from 12 to 36 months, with two of the eight keloids recurring. Chowdri et al.⁸⁶ presented a series of patients with 37 keloid scars treated with intraoperative triamcinolone, and weekly postoperative injections for 2–5 weeks, and then monthly injections for 4–6 months, depending on symptomatic relief. All patients had symptomatic relief by 5 weeks post-surgery, and 92% of patients had no recurrence (mean follow up of 30.5 months).

Mitomycin C 

Mitomycin C is an anti-neoplastic agent, produced by Streptomyces caespitosus that has an antiproliferative effect on fibroblasts.⁸⁷ LOE-4 studies have reported positive⁸⁷ and negative⁸⁸ findings using post-excisional mitomycin C therapy, however both were small case series.

Verapamil 

Verapamil is a calcium-channel antagonist, and has been shown to inhibit collagen synthesis⁸⁹ as well as increase collagenase activity.⁹⁰ Copcu et al.⁸⁹ provided positive level 4 evidence for the efficacy of intralesional verapamil injection intra- and postoperatively. Another LOE-4 study⁹¹ has reported efficacy after excision, when used in conjunction with pressure therapy. D'Andrea et al. conducted a case control study⁹² that included 44 patients that were assigned equally into two treatment arms matched for lesion site and age. The first group was treated with post-excisional topical silicone sheets and intra- and postoperative intralesional verapamil hydrochloride injections; the control group received the same treatment except for verapamil injections. At the 18 month follow-up visit, 12 patients (54%) were keloid free in the verapamil group, whereas no complete regression was achieved in any subject in the control group. The protocol reported the use of other assessments including scar size, thickness, texture and symptomatology, but did not report the methods used to conduct these, or the results of these in detail.

Interferon 

Two RCTs⁹³, ⁹⁴ found post-excisional interferon therapy was less effective than adjuvant therapy with saline⁹³ or post-exicisional steroid therapy.⁹⁴ The former study evaluated interferon-gamma and the latter, interferon-alpha2b, however both had a small sample size and the randomisation technique and blinding of assessments were not reported. A retrospective cohort study⁹⁵ found that post-excisional interferon-alpha2b therapy was more effective than post-excisional steroids or excision alone. However, analysis in this study was conducted on the basis that all patients lost to follow up had a recurrence, which is a major assumption. In addition, recurrence rate was used as the outcome measure despite a short mean follow up for the groups (6.5–7.9 months).

5-Fluorouracil 

One RCT⁹⁶ evaluated post-excisional 5-FU and found it more efficacious than post-excisional injection with saline. Randomisation technique was specified and blinded assessments using a non-validated keloid score were carried out up to 6 months. However, no recurrence data were provided and on average only 50% of patients attended each visit.

Imiquimod 

Imiquimod cream is an immunomodulator; it induces interferon-alpha at the site of application, which is known to be anti-fibrotic.⁹⁷ One comparative study found topical imiquimod cream to be more effective than steroids after shave excision of earlobe keloids⁹⁸ but included only four patients, and a case series⁹⁷ also provided positive level 4 evidence for efficacy.

Pressure 

The mechanism by which pressure therapy affects keloids is unclear, however it is thought that the consequent localised hypoxia results in fibroblast degeneration and cell breakdown.⁹⁹ Only one LOE-4 study¹⁰⁰ was retrieved providing positive evidence for the efficacy of pressure therapy after surgical excision. In this case series¹⁰⁰ of 57 patients, steroid-impregnated tape was applied after earlobe keloid excision and held in place using a large clip-on earring, resulting in only four recurrences in a 4 year follow-up period.

Radiotherapy 

Irradiation is thought to affect connective tissue stem cells, extracellular matrix gene expression, and normal skin and keloid fibroblasts; by destroying enough cells, irradiation may restore a balance between collagen synthesis and degradation.⁹

Out of 27 studies retrieved, evaluating post-excisional radiotherapy, only two studies provide level 2 evidence for efficacy. Sclafani et al.¹⁰¹ conducted a RCT using 42 patients with 50 earlobe keloids. Keloids in the corticosteroid arm (n=12) were treated with 0.4ml of 40mg/ml triamcinolone intraoperatively, and three additional injections postoperatively; the second group (n=16) received the total dose of radiation in one fraction postoperatively (random assignment to 10Gy or low dose 7Gy) using either superficial X-rays or electron beams. Three keloids received surgical excision only. No major difference in recurrence rate (assessed after minimum 12 months follow up) was found between the groups, although the low trial completion rate precluded any definitive statistical analysis. Darzi et al.³⁶ found post-excision beta radiation therapy alone to be as effective as pre- and postoperative radiation in terms of recurrence rate (4Gy given twice a week to a total of 16Gy in both groups).

The remaining 25 studies¹⁰², ¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ¹¹¹, ¹¹², ¹¹³, ¹¹⁴, ¹¹⁵, ¹¹⁶, ¹¹⁷, ¹¹⁸, ¹¹⁹, ¹²⁰, ¹²¹, ¹²², ¹²³, ¹²⁴, ¹²⁵, ¹²⁶ provide positive level 4 evidence for the use of adjuvant radiotherapy after keloid excision. Radiotherapy doses in these studies have ranged from 3 to 40Gy, in either single or multiple fractions. There is no consensus regarding the optimal fraction dose or schedule; some investigators believe that the total dose of irradiation is more important than the timing¹⁰⁵, ¹⁰⁷ or fraction size of the irradiation.¹⁰⁷ Doornbos et al.¹⁰⁷ reported a trend towards a dose-related response between 9 and 15Gy, with higher doses being more effective in terms of recurrence rate. Others report no dose-response effect¹⁰⁵, ¹¹², ¹¹⁷ and a few studies³⁶, ¹¹⁹, ¹²² have suggested that radiotherapy given early is more effective. Different types of radiotherapy have been evaluated, for example superficial X-rays,¹⁰², ¹⁰³, ¹⁰⁵, ¹⁰⁶, ¹¹⁴, ¹¹⁵, ¹²¹ electron beam radiation,¹⁰⁵, ¹⁰⁸, ¹¹², ¹²¹, ¹²³ orthovoltage therapy,¹⁰⁷, ¹¹², ¹²⁰ beta-radiation³⁶, ¹⁰⁹, ¹²⁶ and brachytherapy.¹¹¹, ¹¹⁶, ¹¹⁷, ¹¹⁸, ¹²⁴

Combination adjuvant therapy 

A retrospective cohort study¹²⁷ found excision followed by combination of steroid and radiation therapy or steroid and silicone gel therapy resulted in less recurrence than post-excisional steroid alone. The comparative groups were not well defined and follow up was inconsistent, but greater than 2 years. Positive level 4 evidence has been provided for the use of post-excisional steroid with pressure therapy,¹⁰⁰, ¹²⁸ post-excisional steroid with silicone sheets,¹²⁹ post-excisional verapamil with pressure⁹¹ and post-excisional verapamil combined with silicone sheets.⁹²

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Other therapy 

An LOE-4 study reported positive use of primary radiotherapy in the treatment of keloids¹³⁰; LOE-4 studies have also supported the use of bleomycin,¹³¹, ¹³² retinoic acid,¹³³, ¹³⁴ non-silicone cream with adhesive dressing¹⁶ and adhesive zinc tape.¹³⁵ A RCT¹³⁶ found that hydrocolloid dressing was as effective as moisturiser in reduction of pruritus, but the study was limited by short term follow up, small sample size and no report of randomisation technique and whether assessments were blinded to treatment.

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Discussion 

Despite the significant psychological and functional burden of keloid scarring, overall the research conducted to evaluate therapeutic options has been poor. The RCT is widely accepted as the highest level of study design that is least likely to mislead, by controlling for the known and unknown variables that can introduce bias. As such, RCTs are thought to be the best method of comparing effectiveness of different therapeutic interventions and therefore useful in making decisions about an individual patient's care.¹³⁷ Our study found only 13 RCTs out of 112 studies conducted over the last 25 years and all of these were deemed to be low quality. The vast majority of studies 99/112 (88%) provided level 4 evidence. Amongst the comparative studies, very few described comparison with placebo treatments, even though suggestions for achieving this include using intralesional saline solution injections, sham radiation therapy or even low energy laser therapy that is not expected to have a clinical effect.¹⁰ In addition, comparison of findings between different studies was difficult because of the lack of uniformity in the period of follow up and the techniques used to assess outcomes. A recent Cochrane review³¹ determining the effectiveness of silicone gel sheeting in the treatment and prevention of keloid and hypertrophic scarring concluded that most studies are of poor quality and so the efficacy of silicone gel sheets is unclear. In a comprehensive review of therapeutic options for keloid scarring, Shaffer et al.¹⁰ also found many problems with the designs of existing studies.

Limitations of our study include possible selection bias in excluding non-English articles and studies prior to 1980. Despite this, however, it is clear that the majority of evidence for various keloid treatments is based on level 4 studies and this is not ideal in making evidence-based decisions on an individual's treatment options. Based on the evidence obtained from this review, intralesional steroids (possibly in combination with cryosurgery), silicone gel sheeting, PDL and post-excision radiotherapy seem to be promising areas of therapy that need to be evaluated more rigorously with high quality RCTs (LOE-1), or large prospective well-designed cohort studies (LOE-2).

Several reasons have been cited for the lack of RCTs in the surgical literature, including patient preference, difficulty in standardising and blinding surgical treatment, lack of enthusiasm from surgeons and lack of funding.¹³⁸ However, many of the therapeutic options for keloid scarring are non-surgical and could easily lend themselves to evaluation by a RCT.

When designing such studies, certain factors should be taken specifically into account, including sample size, scar type (keloid vs hypertrophic) and scar assessment. Recruiting enough patients for a large enough sample size can be a problem with single-centre studies, and so a concerted effort for multi-centre collaboration is required. In addition, recruitment should involve patients with keloid scars only. Few studies make a clear distinction between keloids and hypertrophic scars and in studies that do, there is still a lack of detail about patient demography, including age and ethnicity, the anatomical site, cause and age of the scar, family history of scarring and the total number of scars. Keloid scars in different anatomical sites and characteristic morphological features may behave and respond differently to various treatment modalities.¹³⁹, ¹⁴⁰, ¹⁴¹

In a comprehensive review¹⁴² of basic science research studies evaluating keloid and hypertrophic scarring, the significant immunohistochemical and morphologic differences between the two scar entities and the significant heterogeneity within each scar type, during different stages of the scar's evolution, were highlighted. The use of the terms ‘hypertrophic response’ and ‘keloid diasthesis or disposition’ was recommended, and the authors suggested that studies should be based on accurate molecular characterisation of the scar type related to the clinical history and subsequent response to treatment. The variable response to treatment reflects the heterogeneity within keloid scars and future studies may have to first identify cohorts of scar according to molecular profiles, before assessing response to different therapeutic interventions and arriving at conclusions on efficacy. These important concepts have not been adequately addressed in the clinical studies to date.

A consensus agreement should be sought for methods used to distinguish keloid and hypertrophic scarring and studies should be designed to evaluate the treatment of these two entities separately.

Notwithstanding the relevance of RCTs in assessing treatment modalites, an objective method of assessing scars has to be universally employed to make sense of various results obtained following treatment. Assessments of efficacy should be blinded and involve the use of validated and standardised clinical scar assessments, for example the Manchester Scar Scale¹⁴³ or Patient and Observer Scar Assessment Scale,¹⁴⁴ patient reported outcomes, as well as objective measures of scar quality, such as spectrophotometry to assess scar colour and redness,¹⁴⁵ and three-dimensional assessments of scar volume.¹⁴⁶ Studies using recurrence rate as the primary outcome measure should clearly define how recurrence is assessed and ensure a minimum of 12 months follow up. In all cases, outcome measures should be well defined prior to commencement of the study and carried out in a standardised way to allow cross-study comparisons and facilitate meta-analyses.

Although an increase in the use of RCTs is required, subsequent reporting is also critically important, since lack of information regarding methodology and analysis can give the impression that the study was faulty and quality cannot be reliably assessed. Future studies evaluating keloid therapy should take into account the Consolidated Standards of Reporting Trials (CONSORT)¹⁴⁷ checklist, which has been adopted by several major medical journals to aim for complete transparency regarding design, conduct, analysis and interpretation of trials. CONSORT aids the assessment of trial quality and facilitates statistical analysis of outcome data when conducting meta-analyses.¹⁴⁸

In summary, this study has showed that high quality research in evaluating keloid therapy is lacking, with the majority of studies providing no more than level 4 evidence. There is a definite need for well designed and properly reported randomised controlled trials, to provide clinicians with a sound body of evidence that, when combined with clinical experience, can provide patients with optimal management of their keloid scars. Regardless of study design, future studies must clearly differentiate between the treatment of keloid and hypertrophic scars but, furthermore, may also have to carefully subdivide cohorts of keloid scars based on molecular, morphological and immunohistochemical profiles before assessing the efficacy of different treatment modalities.

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