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What is photodynamic therapy?
Photodynamic therapy (PDT) is a treatment modality that has been developing rapidly within various medical specialties since the 1960s. Photoreactive chemicals are injected into the patient and irradiated with light strong enough to activate the chemicals, causing them to emit free radicals and destroy the targeted abnormal cells. An understanding of the principles of photobiology and tissue optics is necessary to understand how it works. Originally used to treat certain malignancies, it is currently being used in the treatment of some forms of macular degeneration, and various skin conditions including basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs), actinic keratoses, Bowen's disease, psoriasis, cutaneous T-cell lymphoma, acne and photorejuvenation of wrinkles.
How does it work?
The photodynamic effect requires:
A chemical photosensitiser
- The majority have a heterocyclic ring structure similar to chlorophyll or haem in haemoglobin.
- Adequate tissue levels are required for the effect to work.
- The drug can be given systemically, topically or directly into the organ. Topical administration for superficial lesions has less risk of systemic side-effects.
- The selectivity of the drugs for different hyper-proliferating tissues varies. For example, sodium porfimer is distributed to connective tissue and blood vessels, whereas 5-aminolaevulinic acid (ALA) concentrates in mucosal layers.
- Choice of photosensitising drug thus depends on the nature of the lesion to be treated.
Light of the appropriate wavelength
- Each photosensitiser has a particular spectrum of action requiring light of the appropriate wavelength for maximum absorption and effect.
- Clinically used sensitisers work between 420 nm (blue) and 780 nm (deep red). Longer wavelengths penetrate deeper (blue 1-2 mm and red more than 5 mm). Newer agents are likely to work with the clinically more penetrating longer wavelengths.
- This is required for effect and hence well perfused and oxygenated tissue is required for the technique to work.
Energy is transferred in the form of light via the intracellular photosensitiser to oxygen molecules. The oxygen then forms highly reactive intermediaries. These have a short half life (fractions of a second) and thus have a very localised tissue-damaging effect. The energy involved is low (so that hyperthermia is unlikely) and damage to adjacent organs is therefore unlikely.
What are the potential advantages of photodynamic therapy?
The potential advantages of PDT are:
- Scarring is unlikely, as collagen and elastin are unaffected, leaving organs intact.
- Highly selective tissue necrosis. This is achieved by:
- Localising the drug to the proliferating tissue.
- Selective uptake of photosensitisers to particular tissue layers.
- Precise directing of laser light using optical fibres.
- Resistance to treatment does not develop with repeated treatment.
What are the limitations of photodynamic therapy?
There are a number of limitations to the technique:
- It requires direction of the light to the appropriate site and tissue depth in order to be effective.
- It is ablative and does not yield material for histological diagnosis. Diagnosis should be made before treatment.
- It is complex, requiring optimal light delivery with laser, and collaboration and co-ordination between clinicians.
- Persistent skin photosensitivity, lasting weeks with some photosensitisers, limits use.
- Availability of the necessary light sources has been a problem. Now low-cost portable light sources are more readily available.
The experience of PDT will vary from person to person. How the treatment is given and the side-effects produced vary according to:
- What part of the body is treated.
- The type of photosensitising drug given.
- The time between giving the drug and applying the light.
- The skin sensitivity to light following treatment.
Licensed indications are as follows:
This is being used more often and is probably the most common form of PDT used. 5-ALA is the main agent used. Current evidence indicates topical PDT to be effective in:
Note that topical PDT alone is a relatively poor option for both nodular BCC and SCC.
There is growing evidence of benefit in acne. Use in SCC is not recommended.
This is briefly that:
- There are no major safety concerns associated with PDT for non-melanoma skin tumours (including pre-malignant and primary non-metastatic skin lesions).
- Evidence of efficacy of this procedure for the treatment of BCC, Bowen's disease and actinic (solar) keratosis is adequate to support its use for these conditions (provided that the normal arrangements are in place for consent, audit and clinical governance).
- Evidence is limited on the efficacy of this procedure for the treatment of invasive SCC. Recurrence rates are high and there is a risk of metastasis. Clinicians should ensure that patients understand these risks and that re-treatment may be necessary.
- Porfimer sodium is licensed for use in PDT for non-small cell lung cancer and obstructing oesophageal cancer. National Institute for Health and Care Excellence (NICE) guidance is available for use in:
- Advanced bronchial carcinoma.
- Localised inoperable endobronchial carcinoma.
- Advanced oesophageal carcinoma.
- Temoporfin is similarly licensed for advanced head and neck cancer. NICE guidance is available for use in parotid carcinoma.
- Verteporfin is licensed for use in age-related macular degeneration associated with mainly subfoveal choroidal neovascularisation (CNV) or with pathological myopia as in the NICE guidelines.
The scope of PDT can be appreciated by considering the full range of conditions for which it has been used with varying degrees of success:
Superficial epidermal lesions
- Skin lesions in particular sites where skin contraction, scarring and ulceration are likely with alternative techniques. Such sites include the bridge of nose and anterior tibial area.
- BCC: trials show good cosmetic results but longer follow-up is required to assess the rate of recurrence.
- Bowen's disease.
- Trials have taken place in SCC and malignant melanoma.
- Cutaneous T-cell lymphoma.
- Kaposi's sarcoma.
Superficial mucosal lesions
- Urothelial disease including superficial bladder tumours.
- Lower genital tract intraepithelial neoplasia (cervical and vaginal).
- Barrett's oesophagus where the avoidance of scarring and stenosis is likely to be valuable.
- Early-stage lung cancer.
- Head and neck malignancy. This includes tumours of the oral cavity, nasal cavity and larynx particularly.
- Early gastrointestinal cancer, particularly stomach and oesophageal cancer.
- Bile duct cancer.
Solid organ cancer
- Prostate cancer recurrences.
- Inoperable cancer of the pancreas. Larger trials have been called for.
- Brain tumours. Glioblastomas and astrocytomas where treatment options are few have been treated with PDT. The preservation of healthy brain tissue makes the PDT attractive. Some success has been reported.
- Small ocular tumours.
- Mesothelioma. Treatment is administered intrapleurally.
- Age-related macular degeneration (the leading cause of blindness in the UK).
- Restenosis after coronary angioplasty.
- Psoriasis, both skin and joint disease.
- Endometrial ablation for menorrhagia.
- Acne vulgaris.
- Viral warts.
- Hair removal.
- Sebaceous gland hyperplasia.
Note: NICE has recommended that all patients with 'wet' age-related macular degeneration with classic subfoveal CNV with at least 6/60 vision, should be considered for PDT.
Research in the areas outlined above may consolidate use clinically in more cancers. The repertoire of PDT therapies available is likely to be further extended with:
- Linking with diagnostic techniques (photodynamic diagnostics).
- Use in non-malignant conditions.
- Hepatic impairment (if severe).
In PDT, the lesion is prepared by removing overlying crust and scale. A photosensitising agent is applied to the lesion and a margin of the surrounding skin. The lesion is illuminated by light of an appropriate wavelength to activate the photosensitiser, producing targeted tumour destruction. Occasionally, the photosensitising agent may be given intravenously (IV). More than one lesion may be treated in a session and the treatment can be repeated.
- A photosensitising cream will be applied to the affected area of skin.
- You will then need to wait for approximately 4-6 hours before being treated.
- Treatment with the PDT light will last 20-45 minutes, after which a dressing will be put on to cover the area and protect it from light.
- Usually only one treatment is needed, but occasionally two or three further treatments may be given.
- Possible side-effects of PDT for skin cancer:
- Pain may be significant with large areas. You will be given a local anaesthetic before your PDT, to prevent pain. For many people this is all that they will need. You may be given steroid cream to apply to the area if it hurts when you are at home.
- Sensitivity to light. The treated area of skin will be sensitive to daylight and bright, indoor lighting. This effect will probably last for between 24-36 hours. You will need to keep the treated area of skin covered during this time. After that you can wash, bathe or shower as usual, but you will still need to treat your skin gently and not rub the area until it has healed.
- Healing - a scab will form on the treated area. The scab usually falls off after about three weeks. As PDT heals quickly without scarring, the appearance after treatment is usually very good.
Given by IV injection. It accumulates in malignant tissue and is activated by laser light to produce a cytotoxic effect. It is given for obstructing oesophageal cancer (but not if there is a malignant fistula) and non-small cell lung cancer. It is effective in ablating high-grade dysplasia and intramucosal adenocarcinoma and T1b/T2 carcinomas complicating Barrett's oesophagus. The main complications are oesophagitis, photo-reactions and stricture requiring dilatation. It is also effective for lung cancer. In one case, a 75-year-old man with emphysema and a tumour of the right intermediate bronchus had four months' treatment and the tumour disappeared with no recurrence for three years. It is safe for patients with poor pulmonary function.
Given by IV injection for advanced squamous head and neck carcinomas refractory to other treatments, but not for palliative treatment. Side-effects include constipation, local haemorrhage, facial pain and oedema, scarring and dysphagia.
This was licensed in 2000 for the treatment of 'wet' age-related macular degeneration with predominantly classic neovascularisation to treat the new vessels, which grow under the retina and distort vision.
Given by IV infusion. It is a light-sensitive dye taken up into the vascular endothelium of the new vessels. Non-thermal laser is then applied, burning the abnormal vessels. Toxic free radicals destroy the vascular endothelial cells without damaging the overlying retina.
The neovascular membranes are identified by fluorescein angiography. Classic membranes are clearly delineated. Occult membranes are hidden underneath the retinal pigment epithelium. Some lesions may have both classic and occult components.
Photocoagulation of classic extrafoveal vessels (those not directly underneath the fovea at the centre of the macula) can delay the loss of vision in a small number of patients. However, most patients present with subfoveal membranes and, whilst photocoagulation can limit subsequent visual loss, it can cause immediate loss of central vision due to the concurrent destruction of the overlying retina. The most serious adverse outcome (within seven days) is decrease in visual acuity which occurs in about 1 in 50 patients. Patients may need five treatments over two years. Side-effects include visual disturbances, nausea, back pain, pruritus, hypercholesterolaemia and fever.
Although photosensitising drugs are mostly taken up by the cancer cells and are concentrated there, they can also make your ordinary skin cells, or your eyes, highly sensitive to light. People who have had PDT are advised to protect themselves from exposure to sunlight and bright indoor lighting. The duration of sensitivity to light (photosensitivity) varies depending upon which drug is used. The drug temoporfin (Foscan®) is commonly used to treat head and neck cancers and will make you sensitive to direct sunlight for up to two weeks.
Photosensitivity occurs with all IV treatments so for 30 days after administration, skin and eyes must not be exposed to direct sunlight or bright indoor light (or ophthalmic slit-lamp examination). Avoid other photosensitising treatment. It is important to note that sunscreens offer no protection against the photosensitivity.
Further reading and references
Garcia-Zuazaga J, Cooper KD, Baron ED; Photodynamic therapy in dermatology: current concepts in the treatment of skin cancer. Expert Rev Anticancer Ther. 2005 Oct
Huang Z; A review of progress in clinical photodynamic therapy. Technol Cancer Res Treat. 2005 Jun4(3):283-93.
Guidelines for topical photodynamic therapy (update); British Association Of Dermatologists (2008)
Photodynamic therapy for non-melanoma skin tumours (including premalignant and primary non-metastatic skin lesions); NICE Interventional Procedure Guidance, February 2006
Photodynamic therapy for advanced bronchial carcinoma; NICE Interventional Procedures, August 2004
Photodynamic therapy for localised inoperable endobronchial cancer; NICE Interventional Procedures, November 2005
Palliative photodynamic therapy for advanced oesophageal cancer; NICE Interventional Procedure Guideline, January 2007
Interstitial photodynamic therapy for malignant parotid tumours; NICE Interventional Procedures, April 2008
Guidance on the use of photodynamic therapy for age-related macular degeneration; NICE Technology Appraisals, September 2003
Bath-Hextall FJ, Perkins W, Bong J, et al; Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev. 2007 Jan 24(1):CD003412.
Photodynamic therapy for Barrett's oesophagus; NICE Interventional Procedure Guidance, June 2010
Photo-dynamic therapy for early oesophageal cancer; NICE Interventional Procedure Guidance, December 2006
Photodynamic therapy for bile duct cancer; NICE Interventional Procedure Guidance, July 2005
Huang Z, Xu H, Meyers AD, et al; Photodynamic therapy for treatment of solid tumors--potential and technical challenges. Technol Cancer Res Treat. 2008 Aug7(4):309-20.
Qiang YG, Yow CM, Huang Z; Combination of photodynamic therapy and immunomodulation: current status and future trends. Med Res Rev. 2008 Jul28(4):632-44.
Photodynamic therapy (PDT); Macmillan Cancer Support
Foroulis CN, Thorpe JA; Photodynamic therapy (PDT) in Barrett's esophagus with dysplasia or early cancer. Eur J Cardiothorac Surg. 2006 Jan29(1):30-4. Epub 2005 Dec 6.
Kondo K, Miyoshi T, Takizawa H, et al; Photodynamic therapy for submucosal tumor of the central bronchus. J Med Invest. 2005 Aug52(3-4):208-11.
No authors listed; Can verteporfin help in macular degeneration? Drug Ther Bull. 2001 Apr39(4):30-2.
Wormald R, Evans J, Smeeth L, et al; Photodynamic therapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2005 Oct 19(4):CD002030.
Summary of Product Characteristics (SPC) - Visudyne® 15 mg, powder for solution for infusion; Novartis, electronic Medicines Compendium, October 2012