Why Are Cancer Drugs Used in Keloid Treatment?

Keloids are thick, raised scars that grow beyond the original wound edges and may keep expanding for years. They often cause:

* Pain and itching

* Redness and prominent vascularity

* Cosmetic and sometimes functional problems (pulling, tightness, restriction of movement)

Unlike hypertrophic scars (which usually stay within the wound and may slowly regress), keloids:

* Show uncontrolled fibroblast activity

* Invade into surrounding normal skin

* Have a high recurrence rate after many conventional treatments

Because of this tumor-like behavior, many authors describe keloids as a form of “benign skin tumor” rather than just “thick scars”.

That similarity to tumors is the main reason why anticancer strategies (chemotherapy, radiotherapy) have been adapted for keloid management.

Traditional intralesional steroid injections (e.g. triamcinolone) can soften and flatten many keloids, but:

* Recurrence rates with steroid alone can still exceed 50% in some series

* Steroids may cause atrophy, telangiectasia, hypopigmentation if used aggressively

Chemotherapy agents like 5-fluorouracil (5-FU) and bleomycin attack the overactive scar cells from a different angle:

* They interfere with DNA synthesis and slow down abnormal fibroblast proliferation

* They help shut down the excessive blood vessel network (angiogenesis) that feeds the keloid

Instead of simply “shrinking” the scar temporarily, the goal is to remodel the tissue and keep the residual keloid cells suppressed over the long term – similar to long-term cancer control strategies.

5-Fluorouracil (5-FU) is a pyrimidine analogue – a classic chemotherapy drug that interferes with DNA synthesis. In keloid management, its main actions are:

* On endothelial cells:
Induces apoptosis (cell death) in endothelial cells and disrupts abnormal neovascular networks inside the keloid.

* On fibroblasts:
Inhibits fibroblast proliferation, migration, and collagen/matrix production – the key drivers of keloid growth.

The combination of these effects reduces the “fuel” (blood supply) and the “engine” (fibroblasts) of the keloid.

Historically, 5-FU was injected at high concentrations (40–50 mg/ml) once weekly for 12–16 weeks. These regimens showed good flattening but were associated with:

* Significant pain

* Ulceration and superficial necrosis of the scar in a notable proportion of patients

A key insight from Liu et al. (2020) and others was that for a disease with chronic, tumor-like behavior, the aim should not be to burn the lesion quickly, but to treat it gently and persistently over years.

They therefore proposed a low-dose, long-term strategy:

* 5-FU concentration: typically 1.5–5 mg/ml (much lower than classic 40–50 mg/ml)

* Steroid concentration: typically 3–9 mg/ml triamcinolone in the same syringe

* Injected intralesionally at intervals that gradually lengthen over time

This approach is designed to inactivate and remodel keloid tissue, not to destroy it aggressively.

Recent reviews and guidelines echo this, recommending low-dose 5-FU (1.5–5 mg/ml) combined with steroids (3–9 mg/ml) as a practical and safer range for long-term use.

In the protocol described by Liu and colleagues (over 10,000 keloid cases since 2002), low-dose 5-FU is used in a planned, stepwise way:

1. Route of delivery:

    * 5-FU is given as intralesional injections directly into the keloid.

    * Often mixed in the same syringe with triamcinolone and a small amount of lidocaine to reduce pain.

2. Starting phase (more active disease):

    * Higher end of the low-dose range (e.g. ~3–4 mg/ml 5-FU + ~8–9 mg/ml triamcinolone).

    * Injections roughly every 4 weeks for several months.

3. Consolidation phase (keloid softer, flatter, less red):

    * Gradual reduction in steroid dose to avoid atrophy.

    * 5-FU adjusted up or down according to vascularity/activity.

    * Injection interval extended to every 6–10 weeks.

4. Maintenance / relapse-prevention phase:

    * Further dose reduction plus injections every ~12 weeks.

    * Total treatment duration often 2–3 years, sometimes longer for very stubborn cases.

5. Micro-recurrences / nodules:

    * Small “reawakening” nodules are injected again at 6–12-week intervals until they are quiet.

The philosophy is very similar to oncology:

Flattening and softening alone does not mean the keloid is cured – it may simply be suppressed under drug pressure. If all treatment stops too early, residual cells can “wake up” and trigger recurrence.

Long-term, low-dose therapy aims to keep that pressure on until residual cells are either eliminated or remodeled into a more normal scar phenotype

Besides 5-FU, other anticancer agents have been used off-label for keloids, including bleomycin and mitomycin C.

* Bleomycin

    * Often used as intralesional injections (e.g. around 1.5 IU/ml in some protocols).MDPI

    * Can be effective but tends to be more painful and has its own toxicity profile, so it is usually reserved for selected cases in experienced hands.

* Mitomycin C

    * More often applied topically at surgery sites or used in specific locations (e.g. around mucosal areas) under specialist supervision.

Compared to these, 5-FU has the most extensive clinical data and is the workhorse chemotherapy agent in many keloid clinics worldwide.

Chemotherapy for keloids is not only used to shrink existing scars, but also to prevent new keloids from forming after surgery.

In the low-dose 5-FU model:

1. Surgical excision

    * Keloids larger than ~2 cm that can be closed primarily are often excised.

    * The wound is closed with multilayer sutures and a tension-reduction device (e.g. “zipline”) to minimize mechanical stress.

2. Intra-operative chemotherapy

    * The fresh wound bed is irrigated with low-dose 5-FU (≈3 mg/ml) + triamcinolone (≈8 mg/ml), then excess fluid is removed before final closure.

3. Early radiotherapy

    * Electron beam radiotherapy is started within 24 hours after surgery (e.g. 4–5 Gy/day for 4 days) to suppress early keloid cell regrowth.

4. Post-operative low-dose 5-FU injections

    * High-risk patients (multiple keloids, prior failures) may receive 5-FU injections into the wound area every 4 weeks for about 6 months, then “on demand” if early symptoms (itching, redness, pain) appear.

    * Lower-risk patients may only receive 5-FU if these early signs appear.

This “prevention model” often allows good results within about 1 year, compared to the multi-year course needed when treating very large, established keloids with injections alone.

Intralesional steroids (e.g. triamcinolone) have been the traditional first-line injection for keloids and HTS. They:

* Reduce inflammation

* Help degrade collagen and other matrix components

* Soften and flatten the scar

However, steroids alone:

* Do not fully address the abnormal vascularity and fibroblast overgrowth

* Carry a risk of tissue atrophy and pigment changes if used at high dose

When combined with 5-FU:

* 5-FU targets fibroblasts and blood vessels

* Steroids help with collagen degradation and symptom control

* Pain with 5-FU injections can actually be less when steroids and lidocaine are added to the syringe

Systematic reviews and meta-analyses suggest that 5-FU + steroid is more effective than steroid alone, with better flattening and lower recurrence, although treatment often needs to be repeated over a prolonged period.

* Keloids behave in many ways like benign skin tumors, with uncontrolled growth, invasion into normal skin and high recurrence rates.

* This tumor-like behavior is why anticancer strategies, including low-dose chemotherapy with 5-FU, have become part of modern keloid management.

* Low-dose intralesional 5-FU (1.5–5 mg/ml), usually combined with triamcinolone (3–9 mg/ml), aims to inactivate fibroblasts and remodel the scar gradually, not destroy it aggressively.

* Long-term, carefully adjusted treatment (often 2–3 years or more) and early management of small recurrences are crucial for reducing relapse.

* Combining surgery + radiotherapy + low-dose 5-FU can significantly reduce postoperative recurrence in selected patients.

* These treatments are highly specialized and should be planned and monitored in an expert setting.