RADIOTHERAPY IN KELOID CARE: EVIDENCE, TECHNIQUES, AND FUTURE DIRECTIONS

Introduction to Keloids: Formation and Clinical Significance

Keloids are benign, elevated scars characterized by excessive fibroblast proliferation and collagen deposition during wound healing. Though non-malignant, these scars can significantly impair quality of life and self-esteem due to their appearance and symptoms. Typically, skin injuries heal with flat, unobtrusive scars. However, disruptions in the wound healing process can lead to the formation of painful, pruritic keloids. These scars may emerge months to years after the initial injury and can grow indefinitely without spontaneous regression.

Wound healing following cutaneous injury involves four phases: inflammation, proliferation, and remodeling. Keloids arise from aberrant wound healing characterized by excessive dermal fibrosis. Prolonged inflammation disrupts the balance between extracellular matrix (ECM) degradation and deposition, leading to excessive collagen and ECM component accumulation. This overabundance in the dermis and adjacent subcutaneous tissue drives the development of hypertrophic keloid scars.

Keloid prevalence varies widely, ranging from 30% to 90% depending on geographic region and ethnicity, with higher rates (4.5–16.15%) in individuals with darker skin tones, particularly non-albino African Americans, Hispanics, and Asians, and those with a family history of keloids. A study on systemic conditions and keloid formation found obesity in 28.57% of keloid patients compared to 10.98% in the general population (P < 0.001), and hypertension in 44.29% versus 15.75% (P < 0.001). Keloids commonly develop in high-tension skin areas, such as the chest, back, shoulders, and lower extremities. Individuals aged 10–30 years are most susceptible, with hormonal changes during puberty or pregnancy further increasing risk.

Intralesional Steroids: Effective but Limited by Recurrence and Complications

Intralesional corticosteroid injections, primarily triamcinolone acetonide (TAC), are the first-line treatment for keloids due to their multifaceted effects on scar pathophysiology:

• Anti-inflammatory action: TAC mitigates the prolonged inflammatory phase of wound healing, a key driver of keloid formation, by suppressing pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) and reducing immune cell infiltration into scar tissue, thereby curbing excessive fibroblast activity.
• Collagen regulation: TAC downregulates collagen gene expression (e.g., COL1A1, COL3A1) and enhances collagenase activity, decreasing excessive collagen and extracellular matrix (ECM) deposition to reduce scar bulk.
• Vascular effects: TAC induces vasoconstriction within the keloid, diminishing vascularity and erythema, which improves cosmetic outcomes.
• Symptom relief: By reducing inflammation and tissue tension, TAC alleviates pain and pruritus, significantly enhancing patient quality of life.

Keloid Removal Treatment success with steroid injection is defined as a reduction in scar volume, height, and associated symptoms such as pruritus and pain. Clinical studies report success rates for TAC monotherapy ranging from 50% to 100%, with most patients experiencing partial to complete scar flattening or symptom relief within 2–6 sessions. However, recurrence rates remain a challenge, ranging from 9% to 50% within 1–2 years, with higher rates in larger keloids, high-tension areas, or patients with genetic predispositions. Common side effects include hypopigmentation (more frequent in darker skin, affecting up to 20–30% of patients), skin atrophy (up to 10–15% with high doses), telangiectasias, and injection pain.

ENHANCING KELOID TREATMENT: THE ROLE OF ADJUVANT RADIOTHERAPY

For mature keloid scars or scars that fail treatment with steroid injection, surgical excision is frequently used, however, as a monotherapy is has a high recurrence rate of 50% to 100%. It is often combined with adjunct treatments such as radiotherapy, which reduces the recurrence rates to 10-29.3%, depending on the radiotherapy modality, dose, fractionation, and follow-up duration.

Understanding Radiotherapy: How It Targets Keloid Formation

Radiotherapy reduces the recurrence of keloids after surgical excision by targeting the cellular and molecular processes driving excessive scar formation. Below is a concise explanation of the mechanism of how radiotherapy works:

• Inhibition of Fibroblast Proliferation: Keloids result from excessive fibroblast activity and collagen deposition during aberrant wound healing. Radiotherapy delivers ionizing radiation to the keloid site, targeting rapidly dividing fibroblasts in the proliferative phase of healing. It induces DNA damage in these cells, leading to apoptosis or cell cycle arrest, thereby reducing the fibroblast population responsible for scar overgrowth.
• Suppression of Collagen Synthesis: Radiation downregulates the expression of collagen-producing genes (e.g., COL1A1, COL3A1) and inhibits transforming growth factor-beta (TGF-β), a key mediator of fibrosis. This reduces extracellular matrix (ECM) deposition, limiting scar bulk and preventing keloid regrowth.
• Anti-inflammatory Effects: Prolonged inflammation is a hallmark of keloid formation. Radiotherapy reduces the inflammatory response by decreasing cytokine production and immune cell infiltration, creating an environment less conducive to excessive scarring.
• Vascular Disruption: Keloids often exhibit increased vascularity, contributing to their erythematous appearance. Radiation damages endothelial cells in microvessels within the scar bed, reducing vascular proliferation and erythema, which improves cosmetic outcomes.

Strategic Timing of Radiotherapy for Keloid Recurrence Prevention

Radiotherapy is most effective when initiated within 24–72 hours following surgical excision of keloids, as this targets the early proliferative phase of wound healing, characterized by peak fibroblast activity and collagen synthesis. By delivering ionizing radiation to the scar bed during this critical window, radiotherapy inhibits fibroblast proliferation and downregulates collagen production, significantly reducing recurrence rates. For instance, a 2021 meta-analysis by Shin et al. found that adjuvant radiotherapy within 72 hours post-excision achieved recurrence rates of 10–29.3%, compared to 50–100% with surgery alone. Modern techniques, such as electron beam radiotherapy (typically 15–20 Gy in 3–5 fractions) and high-dose-rate (HDR) brachytherapy, enhance precision by focusing radiation on the keloid site, minimizing damage to surrounding healthy tissue. A 2024 study of 498 patients treated with electron beam radiotherapy (16 Gy in 4 fractions, started within 24 hours) reported a 26.5% recurrence rate at 68.1 months, with a 89.5% local control rate at 1 year. Delaying radiotherapy beyond 72 hours may reduce efficacy, as fibroblast activity peaks early, underscoring the importance of timely intervention for optimal outcomes.

Targeted Radiation for Keloids: Modalities and Clinical Evidence

Radiotherapy modalities for keloid treatment include external beam radiotherapy (EBRT) with electron beams, brachytherapy using iridium-192, and superficial X-ray therapy. These modalities are typically used post-surgical excision to reduce recurrence rates.

External Beam Radiotherapy (EBRT): EBRT employs electron beams (6–10 MeV) generated by a linear accelerator, the same device used for photon-based treatments in most radiotherapy protocols. Electrons have a shallow penetration depth, typically limited to the dermis, making them ideal for treating superficial keloids while sparing underlying structures like muscle or bone. EBRT is delivered in regimens of 15–20 Gy over 3–5 fractions within 24–72 hours post-excision. A 2024 study of 498 patients treated with electron beam radiotherapy (16 Gy in 4 fractions) reported a 26.5% recurrence rate at 68.1 months, with a 89.5% local control rate at 1 year. Recurrence rates for EBRT typically range from 10–23%, with lower rates for ear keloids (12%) compared to high-tension areas like the chest (34%).

Brachytherapy: Brachytherapy uses a radioactive source, typically iridium-192, to deliver high-dose radiation directly to the keloid bed. It is classified into interstitial or surface brachytherapy. Interstitial brachytherapy involves inserting a hollow catheter into the dermis post-excision, through which the radioactive source is delivered. Surface brachytherapy employs an external applicator secured with adhesive tape to guide the radioactive wire to the skin surface. High-dose-rate (HDR) brachytherapy delivers 12–18 Gy in 1–3 fractions, offering precise dosing with minimal exposure to adjacent tissues. A 2019 study by Jiang et al. reported recurrence rates of 10–15% for HDR brachytherapy, with earlobe keloids showing particularly low recurrence (2–12%). Its efficacy stems from targeted delivery, though its invasive nature and specialized equipment limit widespread use.

Source of photos: https://pmc.ncbi.nlm.nih.gov/articles/PMC5965342/

Superficial X-ray Therapy: Superficial X-ray therapy uses low-energy photon beams (50–150 kV) to deliver radiation to a maximum depth of 5 mm, suitable for superficial keloids. Like EBRT, it minimizes damage to deeper structures but is less precise due to broader beam scattering. Typical regimens involve 12–20 Gy over 3–6 fractions. A retrospective study of 104 keloids treated with soft X-rays (12 Gy in 6 sessions) reported a higher recurrence rate of 23–50%, attributed to less accurate targeting compared to electron beams or brachytherapy, as noted in Mankowski et al. (2017). Its accessibility makes it a viable option for smaller keloids, though it is less effective for larger or high-tension scars.

Radiotherapy’s Drawbacks: Complications in Keloid Treatment
Radiotherapy, particularly as an adjuvant to surgical excision, is effective in reducing keloid recurrence rates to 10–29.3% compared to 50–100% with surgery alone. However, it carries potential complications that clinicians must weigh against its benefits. Below is a detailed overview of complications associated with radiotherapy for keloid treatment.

Acute Complications

• Erythema and Desquamation: Radiation-induced skin reactions, such as erythema (redness) and dry or moist desquamation, occur in 10–20% of patients, typically within 1–2 weeks post-treatment. These are dose-dependent and resolve within weeks with supportive care (e.g., emollients).
• Pain and Discomfort: Localized pain at the radiation site is reported in 5–10% of cases, often transient and manageable with analgesics. Pain is more common with brachytherapy due to catheter placement.
• Wound Healing Impairment: Radiation may delay wound healing post-excision in <5% of cases, particularly with higher doses or in patients with comorbidities like diabetes.

Late Complications

• Hyperpigmentation and Hypopigmentation: Changes in skin pigmentation are common, with hyperpigmentation affecting 10–25% of patients and hypopigmentation in 5–15%, particularly in darker skin tones. These changes may persist for months to years.
• Telangiectasia: Small, dilated blood vessels (telangiectasia) develop in 5–10% of patients, often in areas exposed to higher doses or with repeated treatments. This is primarily a cosmetic concern.
• Skin Atrophy: Thinning of the skin occurs in 2–5% of cases, particularly with superficial X-ray therapy or high-dose regimens, leading to fragility and cosmetic issues.

Rare but Serious Complications

Secondary Malignancy Risk: The risk of radiation-induced malignancy is extremely low (<0.1%) but remains a concern, particularly in younger patients or sensitive areas (e.g., breast, thyroid). Long-term follow-up data are limited, but case reports suggest a latency period of 10–20 years.

• Fibrosis or Tissue Induration: Chronic fibrosis or hardening of irradiated tissue is rare (<2%) but can occur with high doses or in patients with prior scarring.

Conclusion: Advancing Keloid Management Through Radiotherapy

Keloids, driven by excessive fibroblast activity and collagen deposition, pose significant therapeutic challenges due to their high recurrence rates and impact on quality of life. Intralesional corticosteroids, while effective in reducing scar volume and symptoms in 50–100% of cases, are limited by recurrence rates of 9–50% and side effects like hypopigmentation (20–30%) and skin atrophy (10–15%). Adjuvant radiotherapy post-surgical excision addresses these limitations, achieving recurrence rates of 10–29.3% by targeting fibroblast proliferation, collagen synthesis, and inflammation during the critical 24–72-hour post-excision window, as demonstrated in studies like Shin et al. (2021). Modern modalities, including electron beam radiotherapy (10–23% recurrence), HDR brachytherapy (10–15%), and superficial X-ray therapy (23–50%), offer tailored approaches, though clinicians must balance benefits against complications such as erythema (10–20%), pigmentation changes (5–25%), and the rare risk of secondary malignancy (<0.1%). Future research should focus on optimizing dosing protocols, exploring combination therapies (e.g., radiotherapy with biologics like TGF-β inhibitors), and addressing evidence gaps in long-term safety and efficacy, particularly in diverse skin types. By integrating radiotherapy into a multidisciplinary approach, clinicians can enhance outcomes and improve quality of life for patients with recalcitrant keloids.