Dual-wavelength dye laser combined with betamethasone injection for treatment of keloids: protocol of a randomised controlled trial

STRENGTHS AND LIMITATIONS OF THIS STUDY

  • This study aims to explore the potential auxiliary effect of the dual-wavelength dye laser on betamethasone injection and fills a crucial evidence gap regarding the combined treatment of dual-wavelength dye laser and betamethasone injection for patients with keloids.

  • Personnel will receive standard operating procedure training before the commencement of this trial.

  • Experienced physicians will perform the treatments.

  • Owing to the type of interventions, it is not feasible to implement blinding for both patients and treatment providers.

Introduction

Keloids are considered benign fibroproliferative tumours growing beyond the confines of the original wound site, representing excessive proliferation of fibroblasts and the overdeposition of extracellular matrix.1 Keloids often occur on the earlobes, neck, sternum, shoulders and back. They not only affect the appearance but can also cause pain, itching and limited joint movement in severe cases, significantly impacting patients’ mental well-being and quality of life.2 Due to the unclear pathogenesis of keloids, the optimal treatment approach remains elusive. Currently, clinical treatment methods mainly include surgical excision, drug injections, silicone gel compression, radiation therapy and compression therapy.3–5 The limited effectiveness of these treatments and the high recurrence rate6 impose a burden on patients both psychologically and economically.

Betamethasone injection (BI) and pulsed dye laser (PDL) are common minimally invasive treatments for keloids. However, BI has problems with skin atrophy, microvascular dilatation, pain during injection and a high recurrence rate. On the other hand, PDL cannot get satisfactory results when used alone. The mechanism is that the PDL both destroys and inhibits the formation of small vessels within scars.7 It is known that the tissue penetration depth for the PDL is 0.4–1.2 mm.8 Therefore, the PDL cannot be applied to keloid treatment alone because its deep penetration is not deep enough to effectively destroy or prevent dilated capillaries in the deeper regions of the keloids. This may mean that the capillaries in these deeper regions may be able to regenerate and therefore maintain the thickness of the keloid.9–11 Hence, although the laser based on the mechanism of closing microvessels (PDL is the representative technology of this kind of laser) cannot eliminate scar tissue, it may be one of the auxiliary therapies of BI. Steroid injections, on the other hand, can reduce the risk of postoperative pigment deposition after laser procedures.12 13 Therefore, the author suspects that this kind of laser combined with BI may achieve a better curative effect in the treatment of keloids.

The dual-wavelength laser (DWL; 585-nm PDL and 1064-nm neodymium-doped yttrium aluminium garnet (Nd:YAG)) is a derivative technology of PDL that combines PDL and Nd:YAG lasers in one device. The equipment emits two kinds of lasers with different wavelengths in sequence. PDL emits a yellow light pulse of 585 nm, which acts on the haemoglobin (HGB) in the focus to absorb it, thus destroying red blood cells (RBCs) and coagulating capillaries to achieve the therapeutic purpose. When PDL temporarily transforms HGB in the blood into a combination of methaemoglobin and thrombus, the Nd:YAG laser can be absorbed more strongly, which is 3–5 times that of a single wavelength of 1064 nm. In view of the advantages of DWL in closing microvessels, this study uses DWL as an auxiliary therapy for BI.

In this study, a randomised controlled trial was designed, and DWL technology was used before BI, aimed at investigating the potential effect of DWL as an attached therapy for BI and proving the efficacy and safety of DWL+BI in the treatment of keloids, providing a higher level of evidence for this therapeutic approach.

Methods and analysis

Study design

This trial is a prospective, single-centre, parallel positive control, randomised trial designed to evaluate the effectiveness and safety of the DWL (585-nm PDL and 1064-nm Nd:YAG) system combined with BI (diprospan) in treating keloids. Participants will be enrolled according to the trial standards and randomly divided into DWL+BI or BI groups in a 1:1 ratio. Each participant will undergo four treatment sessions over a period of 12 weeks, with each treatment spaced 4 weeks apart. The DWL+BI group will be treated with DWL before BI. To avoid bias in evaluating primary and secondary effectiveness and functional indicators due to participants and evaluators being aware of the trial groups, this clinical trial will blind the outcome assessors.

Data will be collected before intervention (V0), after the first treatment (V1-1), the second treatment (V1-2), the third treatment (V1-3), the fourth treatment (V1-4) and 4 weeks (V2), 12 weeks (V3), 24 weeks (V4) and 52 weeks (V5) after the last treatment. The same equipment will be used during all assessments. Guided by the Recommendations for Intervention Trials 2013,14 the data will be analysed in accordance with the intention-to-treat principle. The study flow chart is shown in figure 1.

Figure 1
Figure 1

Patient flow through the study. DWL, dual-wavelength dye laser; BI, betamethasone injection; LSCI, laser speckle contrast imaging.

Study population

We plan to enrol 66 adult patients who are scheduled to undergo treatment for keloid at Peking Union Medical College Hospital (PUMCH) in Beijing, China. A keloid was defined as excessive scar tissue raised above skin level and proliferating beyond the confines of the original lesion and distinguished from a hypertrophic scar by experienced plastic surgeons according to the following information: the age of the scar (>1 year), starting early or late after trauma, remaining stable or still growing and growing inside or beyond the initial lesion.15 16 Eligible participants must meet the following inclusion criteria: (1) participants diagnosed with keloids by researchers, which can be treated with BI and DWL; (2) keloids with a maximum diameter greater than 0.5 cm but less than 5 cm, and a duration of more than 6 months; (3) adult patients aged over 18 years (4) Fitzpatrick skin types II–IV; (5) seeking improvement in the appearance of their keloids; and (6) willing to sign an informed consent form and agree to complete the follow-up.

Patients who present with the following exclusion criteria will not be eligible for enrolment: (1) participants with active infection in keloids (such as itching, pain, ulceration and suppuration), unhealed wounds or skin diseases in the progressive phase such as vitiligo, psoriasis, etc; (2) those who received or plan to receive treatments or surgeries that could affect the outcome evaluation within 3 months before screening, such as betamathasone, 5-fluorouracil, verapamil, botulinum toxin, laser and radiation therapy; (3) allergic or contraindication to components of betamathasone; (4) participants with a history of coagulation disorders, or those who used or planned to use anticoagulant, antiplatelet or thrombolytic treatment (such as warfarin and aspirin) within 14 days before screening; (5) pregnant, breast feeding, planning pregnancy during the trial (or males unwilling to use appropriate contraception) or those with positive pregnancy test results during screening; (6) with a history of severe organ diseases or active autoimmune diseases; (7) current enrolment in other clinical trials within 30 days before screening; (8) unsuitable for this trial evaluated by researchers due to other systemic diseases or abnormal laboratory test results; (9) unable to communicate or follow instructions and (10) other conditions deemed inappropriate for participation in the trial evaluated by researchers.

Randomisation and blinding

The participants in this study will be randomly divided into two groups: the DWL+BI group or the BI group. This trial uses stratified block randomisation, with random tables generated on a computer using SAS software. The randomisation results will be maintained with strict confidence and securely stored in envelopes. Moreover, two copies of the random table will be sent and stored by the researchers. During participant visits, researchers are required to open the envelopes sequentially and administer the corresponding treatments. The Clinical Trial Endpoint Committee, blinded to the trial intervention, is composed of five members who have over 5 years of clinical trial experience. To avoid potential bias, they will be established to independently assess the primary outcomes of the trial. Any disagreements among members of the committee will be resolved through consensus. In the event that consensus cannot be achieved, a chief supervisor who must have over 5 years of clinical trial experience will be elected to make the final determination.

Interventions

Dual-wavelength dye laser

After cleaning the skin preoperatively, surface anaesthesia with lidocaine cream is applied. Approximately 40 minutes later, the DWL (585-nm PDL and 1064-nm Nd:YAG) system (Cynosure Corp, Westford, Massachusetts, USA) was applied for treatment in this study. Each keloid underwent a two-step treatment, starting with the first pulse of PDL (7-mm spot size, 8.0 J/cm2 fluence and 2 ms pulse duration), followed by a second pulse of Nd:YAG (7-mm spot size, 45 J/cm2 fluence and 15 ms pulse duration) with a medium delay (250 ms) and parallel cooling provided by a cold-air device, regardless of the location, thickness, hardness and blood vessel dilation of the keloid. The treatment endpoint should be the appearance of mild purpura in the keloid. An immediate ice compress lasting for at least 30 minutes should be applied after treatment.

Betamethasone injection

After cleaning and disinfecting the keloids, betamethasone (diprospan; Schering-Plough, Labo NV, Belgium) is diluted with saline to a concentration of 40 mg/mL. After thorough mixing, the solution is drawn with a 1-mL syringe. The needle is inserted into the interior of the keloid. Injection begins after confirming no blood upon withdrawal. The diluted liquid medicine is injected into the scar lesion. The needle is withdrawn while injecting. The liquid medicine should be evenly distributed in the lesion. When the lesion is obviously swollen and the appearance is pale and orange peel-like, the injection can be terminated. According to clinical experience, the injection dose is 0.2 mL/cm3. The amount of injection per person should not exceed 2 mL.

Laser treatment was performed first, and then BI was performed. Because after BI, the lesion was swollen. The water molecules injected into the lesion will interfere with the therapeutic effect of the laser.

Endpoints and definitions

Primary outcome

The primary endpoint of the study is the improvement rate of the Vancouver Scar Scale (VSS) score week 24±15 days (V4) after the last intervention. VSS is a globally acknowledged method for scar assessment17 (online supplemental table 1). The assessment covers four critical dimensions: colour, thickness, vascularity and pliability. If treatment could result in a 1-point increase in the VSS score, which was considered clinically significant improvement.18

Supplemental material

Secondary outcomes

Patient and Observer Scar Assessment Scale (POSAS) is a medical tool designed for evaluating the appearance and sensation of scars.19 It comprises patient self-assessment and observer assessment by healthcare professionals. Patient self-assessment includes aspects such as pain level, itchiness, colour, thickness, softness and overall self-perception, while medical professionals provide a subjective assessment covering aspects like vascularisation, pigmentation, thickness, relief and pliability. All the participants will be presented with photographs of their keloids, both before and 24 and 52 weeks after the intervention. All clinical photographs were taken with a digital single-lens reflex camera (Nikon, Minato, Tokyo, Japan). They will be asked if they observed any improvement before and after participating in the trial. Additionally, participants will assess and rate their satisfaction with the treatment on a 5-point scale (0=no improvement/poor, 1=slightly dissatisfied, 2=neutral, 3=somewhat satisfied and 4=very satisfied).

In addition to the subjective indicator of VSS and POSAS, we also introduced other objective indicators. Laser speckle contrast imaging (LSCI; PeriCam PSI System, Perimed, Jarfalla-Stockholm, Sweden) is a useful tool for measuring the perfusion of keloids. LSCI is based on a speckle pattern since backscattered light from a tissue that is illuminated with coherent laser light forms a random interference pattern at the detector. It demonstrated rich perfusion in the lesional skin in comparison with the normal skin.20–22 The perfusion index of keloids was quantified by the LSCI device and simultaneously generated and analysed perfusion images, intensity images and photos of the scanned area by software (PimSoft V.1.2.2.0; Perimed). Consequently, the average blood flow level within the regions of interest was directly obtained from the device. The measured values were expressed in perfusion units (mL/100 g/min). In a study about using an LSCI machine to evaluate the severity of keloids, the relative perfusion index (RPI) is proposed to replace the perfusion value. RPI is defined as23:

Embedded Image

The blood perfusion levels of the patient’s keloid (Kperfusion) and normal skin (Nperfusion) and the area of the keloid (Karea) were obtained by LSCI. The RPI could better represent the degree of pain, pruritus and status of internal molecular reactions in keloids than could the VSS and blood perfusion levels.

The other objective indicator is the lesion volume. The thickness value will be measured by calliper and the area value will be measured by LSCI.

To sum up, secondary endpoints include:

  1. The improvement rate of VSS score in V2, V3 and V5.

  2. The improvement of the POSAS and the patients’ satisfaction with the treatment in V4 and V5.

  3. The change of relative perfusion index (measured by LSCI) in V4 and V5.

  4. The change of lesion volume (area measured by LSCI, thickness measured by calliper) in V4 and V5.

Safety outcomes

Through observation of adverse events by the researchers and any spontaneously reported adverse signs, symptoms or events by the participants, the safety of DWL+BI will be assessed. Detailed records of the occurrence and percentages of any symptom will be maintained. Injection-related adverse reactions, such as itching, pain, redness, bruising and discolouration within 14 days post-treatment, will be documented as injection-related adverse reactions. Laser treatment adverse events, including itching, pain, redness, bruising and discolouration within 14 days post-treatment, will be recorded. Adverse reactions persisting beyond 14 days and other adverse events will be noted. Participants are encouraged to self-report post-trial health conditions, and physicians will inquire about any discomfort during the trial via telephone or email, recording participant abnormalities post-treatment at various stages to assess treatment safety.

Safety assessment will occur at the following time points: immediately after each treatment, at 4 weeks±7 days after the last treatment, at 12 weeks±15 days after the last treatment and at 24 weeks±15 days after the last treatment.

Observation items will include:

  1. Vital signs: including respiratory rate, heart rate, blood pressure and body temperature.

  2. Laboratory tests: blood count (RBCs, HGB, white blood cells (WBCs), neutrophils, lymphocytes, platelets), urinalysis (RBC, WBC, glucose and proteins), blood biochemical examination (alanine aminotransferase, aspartate aminotransferase, total bilirubin, blood urea nitrogen and creatinine) and coagulation function (prothrombin time (PT)-international normalised ratio, PT and activated partial thromboplastin time).

  3. Pregnancy test (urine or blood): in reproductive-age female participants at randomisation, prior to each treatment and at 24 weeks±15 days after last treatment.

  4. Participants’ self-report of treatment-related adverse reactions 14 days after each treatment.

Researchers will inquire whether any adverse events occurred since the last visit and inquire about concomitant medication and accompanying treatment. Participants will be informed that they can contact researchers at any time for additional visits.

Sample size

According to the data from DWL and BI performed at the department of plastic surgery in PUMCH in 2023 and the previous study,24–26 the improvement rate of VSS in patients with BI is 50%. However, with the combined approach of DWL+BI, the improvement rate of VSS can be elevated to 80%–85%. Considering a significance level of α=0.05, a power of 0.80, randomisation in a 1:1 ratio, and a two-sided statistical test, along with a projected 20% loss to follow-up rate, the anticipated sample size for enrolment in the clinical trial was calculated to be 66 patients.

An anticipated maximum dropout rate of 20% during the study period is considered. This dropout rate includes all cases that cannot be included in the primary analysis, typically referring to instances deemed by the principal investigator as serious study violations (affecting the primary outcomes assessment). Potential events encompass the following scenarios: failure to meet inclusion/exclusion criteria, deviation from the planned treatment in the study, utilisation of treatments not specified, incomplete follow-up, surpassing the stipulated follow-up timeframe or the administration of concurrent treatments influencing treatment efficacy. All of these mentioned situations will be accounted for in the comprehensive dropout rate category.

Statistical analysis

Continuous variables, following a normal distribution, will be presented as mean±standard; otherwise, they will be represented by median and IQR. Categorical variables will be expressed as numbers and percentages. Continuous variables with normal distribution will be compared by Student’s t-test. The Mann-Whitney U test will be employed for continuous variables with skewed distribution. Categorical variables will be compared through the χ2 test or Fisher’s exact test. If there are statistically significant differences in baseline characteristics between the two groups, further evaluation will be conducted. The analysis will be carried out by a dedicated data analyst who is unaware of the subjects’ group allocation. All tests in the study are two-tailed, and statistical significance is defined as p<0.05. This trial does not have predefined interim analyses and corresponding early termination criteria, so this information is not applicable here. All statistical analyses will be conducted after the completion of data collection, sorting and final locking.

Data management and quality control

A well-designed case report form will be employed to gather clinical trial data from eligible patients (online supplemental table 2). Three staff members will be trained to assist in the collection of keloid data by Nikon camera and LSCI. Laboratory test results will be obtained from a digital medical record system. All paper documents are securely stored in PUMCH and must be retained for a minimum of 10 years after the study concludes. The Clinical Trial Steering Committee will verify all observed results and findings in the study to ensure the reliability of the data, ensuring that all conclusions are derived from the original data.

Supplemental material

Throughout this trial, clinical monitors will conduct site monitoring visits to trial centres, ensuring strict adherence to the trial protocol and accurate completion of trial documentation. The researchers participating in this trial are all qualified individuals who have undergone good clinical practice training. Before the trial implementation, uniform standard operating procedure training is provided to all research personnel. This training ensures that each member is familiar with the implementation details and operational procedures.

Patient and public involvement

Patients and the public were not engaged in the design, implementation, or assessment of outcome measures for this study. The research results will be communicated to study participants via telephone and email.

Study status

The trial intends to enrol its first patient in July 2024 and is scheduled to end in February 2026. As of the time of manuscript submission, no participants have been enrolled in the study.

Ethics and dissemination

This study has received approval from the Ethics Committee of Peking Union Medical College Hospital (no. I-24PJ0121) and has been registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn/) under the registry number ChiCTR2400080148. All procedures outlined in this study will be conducted in accordance with the principles of the Helsinki Declaration. The trial results will be published in an international peer-reviewed journal.

Discussion

Keloids, characterised by raised and disfigured tissue resulting from aberrant wound healing, pose a therapeutic challenge due to the multifactorial nature of scar formation.27 Current treatments primarily aim to suppress fibroblast proliferation, curb collagen deposition and alleviate inflammation in addressing keloids. However, these therapies exhibit a propensity for relapse and seldom achieve complete resolution. Multimodal treatment approaches, which underscore the integration of diverse measures to improve therapeutic outcomes, are increasingly being employed in numerous studies and clinical settings.28

In the realm of pharmacological intervention, corticosteroids have long been considered a primary treatment for keloids.29 First, they achieve inflammation suppression by inhibiting the migration and phagocytic activity of WBCs and monocytes.29 Second, as potent vasoconstrictors, corticosteroids effectively reduce the delivery of oxygen and nutrients to the wound bed.29 Third, they exhibit antimitotic effects, inhibiting the proliferation and differentiation of keratinocytes and fibroblasts.29 Additionally, corticosteroids can lower levels of plasma proteinase inhibitors and collagenase inhibitors (such as α-1-antitrypsin and α-2-macroglobulin), thereby promoting the degradation of collagen by collagenase.29 Furthermore, corticosteroids induce regression of keloids by interacting with the glucocorticoid receptor, inhibiting the expression of endogenous vascular endothelial growth factor and fibroblast proliferation.29 Unfortunately, the recurrence rate with sole triamcinolone acetonide injection therapy can be as high as 50%–95%.30 Prolonged and excessive injections may lead to local vasodilation, fat atrophy, skin necrosis, ulcers and complications such as Cushing’s syndrome.30

In recent years, DWL therapy has emerged as a promising approach, bringing new advancements to the treatment of keloids.24 DWL devices combine PDL and Nd:YAG lasers in a single device, using the same transmission system.24 The two laser heads operate independently, maximising their respective roles. PDL emits a 585 nm laser, primarily targeting HGB. It disrupts RBCs, causing capillary coagulation and reducing blood supply to the keloids.31 Simultaneously, it induces a temporary transformation of HGB into high-iron HGB, promoting its combination with the thrombus and thereby enhancing the absorption of Nd:YAG laser.32 The Nd:YAG laser, with its crucial 1064 nm wavelength, allows deep penetration into the dermis and vascular specificity.25

Therefore, in view of the fact that the microvascular relaxation caused by BI may become a potential risk of poor therapeutic effect and high recurrence rate of keloid17, DWL has the potential to become a good helper suitable for BI because of its characteristics of closing the microvascular of keloid.33 DWL+BI may combine laser therapy and hormone injections to leverage their respective advantages, providing a more comprehensive scar treatment. If DWL combined therapy can enhance the curative effect of BI, our team will further design clinical trials in the future and perhaps find the best combined therapy scheme of DWL therapy and BI therapy, so as to reduce the dosage of BI while maintaining the original or even better curative effect. After all, limiting the quantity of injected steroids not only reduces the risk of atrophy and telangiectasias but also minimises pain.

In summary, the treatment of keloids with DWL+BI exhibits potentially higher safety and efficacy. The disadvantages of laser therapy are that plastic surgeons may use it less frequently than dermatologists and have a certain learning curve. Despite the short operation time of laser therapy, medical institutions need to provide laser instruments, which are expensive.

Limitations

Our trial has some acknowledged limitations. First, it is a single-centre trial, and as a result, the findings may not be readily applicable to all centres. Therefore, a future multicentre study with a larger sample size will be essential for broader generalisability. In addition, due to the nature of the interventions, it is not feasible to implement blinding for patients and treatment providers.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by the Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (no. I-24PJ0121). Participants gave informed consent to participate in the study before taking part.

Acknowledgments

We acknowledge all those involved in the study, including practitioners, assessors and participants.

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