1. Introduction

Keloid scars are a cosmetic disorder resulting from aberrant wound healing processes [1, 2]. While the precise etiology of keloid formation remains unclear, existing evidence points to a genetic component in some instances, modulated by patient-specific and wound-related factors [3, 4]. Managing keloid scars poses a clinical challenge due to the absence of a universally effective therapy or standardized treatment regime. Local corticosteroid injections are commonly employed alongside other injectable treatments such as interferon (IFN), 5-fluorouracil (5-FU), bleomycin, and verapamil [3–5].

Despite the widespread use of corticosteroids, some patients exhibit poor responsiveness or encounter adverse effects like telangiectasia, linear hypopigmentation, subcutaneous tissue atrophy, necrosis, skin ulceration, or Cushing’s syndrome resulting from triamcinolone acetate overdose. These complications have prompted researchers to explore alternative therapeutic avenues [5–8].

One promising strategy involves the application of vascular endothelial growth factor (VEGF) inhibitors, which can restrict keratinocyte-derived VEGF activity or downregulate epidermal VEGF in keloid lesions [9]. VEGF is a potent proangiogenic factor facilitating endothelial cell survival, migration, and proliferation [10]. Previous studies have also demonstrated the expression of VEGF in keloid scars [10–13].

Bevacizumab (Avastin®) is a humanized anti-VEGF monoclonal IgG1 antibody approved by the U.S. Food and Drug Administration (FDA) for treating various metastatic malignancies, such as lung, breast, kidney, and brain tumors [14, 15]. Bevacizumab is also under investigation for off-label applications across diverse conditions [15–17].

A double-blind, randomized trial was conducted to assess the potential efficacy and safety of bevacizumab as an adjuvant therapy for keloid scars. This trial is the first controlled study to evaluate the role of bevacizumab in managing keloid scars. Bevacizumab was selected for its anti-angiogenic properties and ability to target VEGF, a key player in keloid development [2, 18]. This study aimed to ascertain the effectiveness and safety of combining bevacizumab with standard keloid treatments.

2. Materials and Methods

2.2. Interventions

The patients were divided into two treatment groups: single therapy and combined therapy group. The single treatment group received 20 mg/ml of intralesional triamHEXAL® (triamHEXAL® 40 mg, Grover, Germany) monthly for three months. In contrast, the combination group received 20 mg/ml intralesional triamHEXAL® monthly for three months plus 2.5 mg/ml of Avastin® (Genentech, Inc., South San Francisco, CA) monthly for two months (Figure 1).

All participants were followed for 12 weeks, and one keloid scar per patient was selected using simple randomization. Injections were administered with an insulin syringe and a 27-gauge needle under aseptic conditions.

3. Results

The study included 38 participants, with an equal distribution of men and women, having a mean age of 35.32 (SD 14.02) years. The average age of keloid onset was 13.2 months, ranging from 2 weeks to 25 months. Participants were divided into two groups: a single therapy group (n = 19) and a combination therapy group (n = 19), with two patients in the latter group lost to follow-up. Initial characteristics such as age, BMI, illness duration, gender, cause, family history, and location were similar between the two groups, as detailed in Table 1.

Clinical outcomes were assessed at various time points throughout the study and compared between the two groups. At baseline, there were no significant differences in mean scores between the two treatment groups (P > 0.05), as presented in Tables 2 and 3. However, all mean scores significantly decreased from baseline to three months after treatment (P < 0.05), as depicted in Table 2. The changes in mean scores from baseline to one month and three months posttreatment did not differ significantly between the two groups, except for the pigmentation score and total score, as outlined in Table 2 and Figures 2 and 3.

Specifically, the mean change from baseline to three months after treatment for the pigmentation score in the single treatment group was 0.60 (95% CI: −1.18, −0.01; P = 0.045) lower than that in the combination treatment group. Similarly, the mean change from baseline to three months after treatment for the total score in the single treatment group was 1.37 (95% CI: −2.68, −0.07; P = 0.039) lower than that in the combination treatment group, as shown in Table 2.

Mean scores with standard errors for study time points by treatment groups are illustrated in Figure 4. Patient satisfaction was evaluated using a visual analog scale (VAS) score, which was significantly higher in the combination treatment group than in the single treatment group, as indicated in Table 3. Furthermore, there was a notable reduction in keloid height in the combination group three months after treatment completion (P = 0.024), as detailed in Table 3. No significant differences were observed in side effects between the combination treatment group and the single therapy group at the end of the three-month follow-up period. Overall, the findings suggest that combination therapy may offer more efficacy than single therapy in treating keloids, resulting in improved outcomes related to pigmentation, total score, patient satisfaction, and reduction in keloid height.

4. Discussion

To assess the efficacy of bevacizumab as an adjuvant therapy to intralesional triamcinolone for keloid treatment, a randomized controlled trial was conducted, monitoring patients for 12 weeks posttherapy completion. Results revealed significant scar height, vascularity, and pliability improvements in both treatment groups. However, the combination therapy group exhibited lesser scar pigmentation and overall scores. Additionally, the reduction in keloid height after three months was notably more significant in the combination therapy group than the single therapy group, with higher patient satisfaction scores.

These findings suggest that bevacizumab is comparably effective and safe as triamcinolone, making it a viable adjuvant treatment for keloids, particularly in cases where corticosteroids are contraindicated. While early stage keloids may benefit from bevacizumab’s anti-neoangiogenic effects, further research is needed to elucidate its impact on mature keloids.

Research on vascular endothelial growth factor (VEGF) inhibitors has explored their role in keloid formation, with bevacizumab potentially inhibiting endogenous VEGF to prevent keloid development. VEGF contributes to keloid formation by three distinct methods: (1) promoting fibroplasia or inflammation, (2) excessive tissue fibrosis through an imbalance in extracellular matrix metabolism [21, 22], and (3) VEGF as a proinflammatory cytokine released during the inflammatory phase of routine wound healing is a strong proangiogenic factor that can lead to aberrant wound healing and excessive tissue fibrosis [22–24].

Despite several animal research studies demonstrating the potential effectiveness of anti-VEGF in treating hypertrophic scares and keloid development, more human clinical trials are needed in this area [25, 26]. However, pathological investigations have shown that keloid tissue contains abnormal levels of VEGF [22, 27–29]. Salem et al. found a significant difference in VEGF expression between individuals with keloid lesions and controls, suggesting that VEGF may play a role in keloid formation [27]. Their findings imply that VEGF could be involved in developing keloids, and inhibiting these biological activities would be necessary in clinical treatment. However, the limited research sample might be a drawback.

Combining corticosteroids and VEGF inhibitors may synergistically reduce VEGF expression, as our study’s outcomes suggested. Pathological analysis by Jiang et al. suggested that VEGF overexpression may be associated with the invasive growth of keloids [30]. The eventual treatment cost of any keloid lesion is impacted by the location and form of the keloid; keloids on the back of the head, sternum, and chest require more treatment sessions and higher steroid doses; therefore, adjuvant therapies like bevacizumab that can reduce keloid height may be promising options for the treatment [31].

The cost-effectiveness of bevacizumab therapy for keloids is promising, considering its low required volume and potential impact on treatment sessions and overall costs. Notably, the observed differences in keloid pigmentation may stem from VEGF regulation and lesion growth control. This study stands out as the first randomized controlled trial to evaluate a novel adjuvant monoclonal therapy for keloids, employing a comparative approach to assess treatment efficacy.

5. Conclusion

This study provides evidence that bevacizumab may be a viable option for treating keloid disorder. However, further research is warranted to validate its effectiveness and safety, especially as a standalone therapy in diverse patient populations. Addressing these limitations in future studies will contribute to a more comprehensive understanding of bevacizumab’s role in managing keloid disorder.

Ethical Approval

This research was approved by the Ethics Committee of the Isfahan University of Medical Science (No. IR.MUI.MED.REC.1398.163), and at the Iranian Registry of Clinical Trials, the study was documented (https://www.irct.ir; IRCT registration number: IRCT20131119015455N5).

Consent

Written informed consent was obtained from the patients.

Disclosure

The abstract of this manuscript was presented as an E-poster in EADV congress-2023.

Conflicts of Interest

The authors declare that they have no conflicts of interest.