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 (see below). Originally used to treat certain malignances, 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.¹

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.
• Oxygen:
  • 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.

The potential advantages of PDT are:

• Lack of scarring. This 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

There are a number of limitations to the technique:

• It requires direction of the light to the appropriate site and tissue depth 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 was 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:

• Topical PDT. This is being used more often and is probably the most common form of PDT used. ALA is the main agent used. Current evidence indicates topical PDT to be effective in:
  • Actinic keratoses on the face and scalp
  • Bowen’s disease
  • Superficial BCCs
  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.³
  

  NICE guidance for topical use is available.4 This is briefly that: There are no major safety concerns associated with PDT for non-melanoma skin tumours (including premalignant and primary non-metastatic skin lesions). Evidence of efficacy of this procedure for the treatment of basal cell carcinoma, 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 retreatment may be necessary.

• Non-topical PDT:
  • Porfimer sodium is licensed for use in PDT for non-small cell lung cancer and obstructing oesophageal cancer. NICE guidance is available for use in advanced bronchial carcinoma,⁵ localised inoperable endobronchial carcinoma⁶ and advanced oesophageal carcinoma.⁷
  • Temoporfin is similarly licensed for advanced head and neck cancer. NICE guidance is available for use in parotid carcinoma.⁸
  • Verteporfin is licensed for use in age-related macular degeneration associated with mainly subfoveal choroidal neovascularisation or with pathological myopia as in the NICE guidelines.⁹

The scope of PDT can be appreciated by considering the full range of conditions² 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 bridge of nose and anterior tibial area.
  • BCC: trials show good cosmetic results but longer follow-up required to assess rate of recurrence.¹⁰
  • Bowen's disease
  • Trials have taken place in SCC and malignant melanoma²
  • 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 valuable¹¹
  • Early stage lung cancer
  • Head and neck malignancy. This includes tumours of oral cavity, nasal cavity and larynx particularly.
  • Early gastrointestinal cancer particularly stomach and oesophageal cancer¹²
  • Bile duct cancer¹³
• Solid organ cancer:¹⁴
  • 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.²
  • Small ocular tumours
  • Mesothelioma. Treatment is administered intrapleurally.
• Benign conditions:
  • Senile macular degeneration (the leading cause of blindness in the UK)
  • Restenosis after coronary angioplasty
  • Psoriasis for 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 choroidal neovascularisation(CNV) with at least 6/60 vision, should be considered for PDT.⁹
• Future prospects. Research in the areas outlined above may consolidate use clinically in more cancers. Linking with diagnostic techniques (photodynamic diagnostics), immunoadjuvants¹⁵ and use in non-malignant conditions is likely further to extend the repertoire of photodynamic therapies available.

• Porphyria
• Breast-feeding
• Hepatic impairment (if severe)
• Pregnancy

Topical 5-aminolaevulinic acid

In PDT, the lesion is prepared by removing overlying crust and scale. A photosensitising agent is applied to the lesion and a margin of 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. More than one lesion may be treated in a session and the treatment can be repeated.⁴

Porfimer sodium

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.¹⁷ 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 4 months' treatment and the tumour disappeared with no recurrence for 3 years. It is safe for patients with poor pulmonary function.¹⁸

Temoporfin (Foscan®)

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.

Verteporfin

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.
It 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.¹⁹

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 7 days) is decrease in visual acuity which occurs in about 1 in 50 patients. Patients may need 5 treatments over 2 years.²⁰ Side-effects include visual disturbances, nausea, back pain, pruritus, hypercholesterolaemia and fever.