Bleomycin and the skin
What is bleomycin?
Bleomycin is an antibiotic derived from the fungus Streptomyces verticillus but is mainly used as a chemotherapy drug. It causes DNA strand scission (breakages in the DNA strand), preventing cell replication.
Bleomycin is mainly excreted from the body via the kidneys. It can also be inactivated in the body by hydrolase enzymes, the level of which varies in different tissues. There is a high rate of skin side effects when used intravenously to treat cancer because skin, in particular, has no bleomycin hydrolase activity.
Skin side effects of systemic bleomycin
Skin side effects develop in approximately 50% of patients receiving bleomycin for cancer.
Common side effects are:
- alopecia (hair loss)
- stomatitis (sore mouth) and more general mucositis
- flagellate erythema (reddish-brown streaks)
Less commonly reported side effects include:
- erythema multiforme
- thick scaly plaques on knees and elbows
- tightening of the skin in the hands resulting in gangrene (sclerotic dermal reactions)
- macules (flat spots) and papules (small bumps) that may be inflammatory
- nail changes including nail loss, nail dystrophy and slowing of nail growth
- neutrophilic eccrine hidradenitis.
Approved uses for systemic bleomycin
Bleomycin is approved by the FDA (Food and Drug Administration in the USA), Medsafe in New Zealand, and similar regulatory authorities in other countries, for the treatment of squamous cell carcinoma of the head and neck, cervix, penis and skin, Hodgkin and Non-Hodgkin lymphoma, testicular cancer and malignant pleural effusion.
It is generally used intravenously for these indications. Other routes of administration for the treatment of cancer include intramuscular and intrapleural injections as it is poorly absorbed after oral intake.
Intralesional injection of bleomycin
The use of bleomycin by injection into specific skin lesions (intralesional) has not been approved by the FDA or by Medsafe in New Zealand. Informed consent to explain this should be obtained before such use. However, there have been multiple clinical trials and case reports in the medical literature describing the use of intralesional bleomycin, documenting the beneficial responses and adverse events.
Bleomycin penetrates through cell membranes poorly. Local anaesthetics disrupt cell membranes so the bleomycin may be made up in local anaesthetic solution (such as lignocaine) to increase its penetration into cells. Electrical impulses are sometimes used to improve bleomycin efficacy via electrodes placed in the skin around the injected area (electrochemotherapy).
What are the indications for intralesional bleomycin?
The most common use of intralesional bleomycin injections is for viral warts that have failed to respond to conventional therapies such as liquid nitrogen cryotherapy and wart paints/gels (e.g., high-strength salicylic acid). It has been used successfully in immunocompromised patients such as organ transplant recipients. It may also be considered for use in difficult-to-treat sites, such as under the nail, or wart types, such as mosaic plantar warts. There have been successful but limited reports of use for treatment-resistant genital warts.
Reported cure rates in placebo-controlled double-blind trials for treatment-resistant warts vary with site:
- plantar warts (‘verrucas’) 47–87%,
- warts around the nails (periungual warts) 76–94%
- elsewhere on the hands and feet 75–77%.
Other skin conditions for which intralesional bleomycin has been used include:
- Vascular anomalies – haemangiomas, venous malformations, lymphatic malformations including cystic hygroma.
- Primary skin cancers – basal cell carcinoma, keratoacanthoma, flat (macular) stage of Kaposi sarcoma and squamous cell carcinoma / Bowen disease have been successfully treated usually with the combination of intralesional bleomycin followed by electrical impulses (electrochemotherapy).
- Metastatic cancers in the skin – skin metastases of melanoma and breast cancer have been reported to respond locally to electrochemotherapy but no longterm followup has been reported. Intralesional bleomycin is not regarded as a substitute for conventional therapy of these conditions, but as palliation.
- Cutaneous leishmaniasis – there have been a very small number of case reports describing the successful use of intralesional bleomycin for this skin infection.
Protocol for the treatment of warts
Bleomycin should only be prepared for use by health professionals experienced in the handling of chemotherapeutic agents.
Warts may be prepared before injection by debulking such as paring down with a scalpel blade.
For the treatment of warts, bleomycin sulphate is usually diluted to 1U/ml (1mg/ml) in normal saline or 1% lignocaine (without adrenaline). The solution is reported to be stable for 4 weeks if kept refrigerated.
The solution is injected into the wart, aiming to see blanching. A number of injection techniques have been reported (see below). Most commonly a 1ml tuberculin syringe and Luerlock 30G needle, or an insulin syringe where the needle is joined to the shaft of syringe, is used. Because of the very folded surface of warts, leakage of solution to the surface is sometimes seen. The usual injected volume is 0.1-2ml per treatment session. The optimal dose has not been determined, but this appears to be a safe and effective range. Injection of many warts in a single session exceeding this dose range may result in an increased risk of side effects.
The wart is re-assessed in 3-4 weeks for possible further treatment. In many of the reported clinical trials, bleomycin was injected on 1-3 occasions, although in one study the average number of treatments per wart was 4.
Side effects and adverse events following intralesional bleomycin
1. Common local immediate side effects:
Bleomycin injections are virtually always painful. General anaesthesia, regional anaesthetic blocks, infiltrative local anaesthesia and topical anaesthetic cream may be used, particularly in children or when multiple injections are required. Jet injectors, modified tattoo machines, monolet needles and pricking through with bifurcated vaccination needles may reduce the pain of the procedure. However, in general, the pain is tolerable and comparable to cryotherapy.
Redness, swelling, pain and a burning feeling are common immediately after the injection. The pain may persist for up to 72 hours and usually responds to paracetamol, sometimes with additional codeine.
2. Common delayed local effects:
It is common for a black scab to form and it falls off after 4 weeks. This can be a useful indicator of effectiveness as it implies tissue death and detachment of the lesion.
3. Uncommon, rare and single reports of local adverse events:
- Narrowing of the fingertips, Raynaud phenomenon, restricted interphalangeal joint movement and gangrene of fingertips have been reported particularly following injections into or close to fingers and toes.
- Nail growth may be restricted following injections around the nail fold. Nails may be lost or damaged with ridges or pigmentation appearing.
- Reduced or loss of pigment in the injected skin, depressed (atrophic) and elevated (hypertrophic) scars have been reported.
- There has been a single case report of lymphangitis (inflamed lymphatic vessels).
- Paraesthesia (tingling) may develop.
- The development of a haematoma at the injection site is an unwanted event usually due to injecting too deeply.
4. Generalised side effects
These have been very rarely reported but include anaphylaxis, itch, urticaria (hives), flagellate erythema / hyperpigmentation and pneumonia-like symptoms. No cases of pulmonary fibrosis (seen with intravenous bleomycin) have so far been reported following intralesional bleomycin.
Contraindications to intralesional bleomycin
Because of the possibility of developing Raynaud phenomenon, it is recommended that intralesional bleomycin is not performed in patients with peripheral vascular disease or connective tissue disease.
The use of bleomycin is not recommended in pregnancy and lactation because of the risks of the drug to the baby. It has been shown to cause birth defects in mice.