Photodynamic Therapy (PDT) and Phototoxicity

Last updated: 25 September 2008.

Introduction

Photodynamic therapyPhotodynamic therapy (PDT) is a treatment modality used in oncology medicine by a variety of specialist physicians to eradicate premalignant and early-stage cancer and reduce the tumour size in end-stage cancers. Click here for more information. (PDT) is a systemic treatment used in oncology by a variety of specialists to eradicate premalignant and early-stage cancer and reduce the tumour size in end-stage cancers. Applied PDT in dermatology is a localized procedure used to treat skin cancers and some other benign skin conditions.

In PDT, a photosensitizing agent is used as well as a focal light source and oxygen to selectively destroy cancer cells through a photodynamic reaction. Photosensitising agents are drugs that become active when light of a certain wavelength is directed onto the anatomical area where they are concentrated. The photosensitizing agent is preferentially taken up into and by cancer cells.

Current evidence is showing PDT to be effective in treating Actinic KeratosesActinic Keratoses are collections of abnormal skin cells found in the upper layers of skin that develop after prolonged exposure to sun light. AKs are precancerous lesions. Click here for more information.(AKs) on the face and scalp, and superficial Basal Cell Carcinomas (BCC). It appears to be as effective as conventional treatments such as cryotherapy (liquid nitrogen), curettage, radiotherapy and topical 5-fluorouracil (Efudix™ cream).

Photosensitizing agents

The photosensitizers used for PDT are either 5-aminolevulinic acid (ALA) or its methyl ester (MAL).  They are applied to the skin covering the area to be treated. Both ALA and MAL are approved in several countries for the treatment of AKs, and in some countries for the treatment of Bowen’s disease and BCC.

Photosensitising agents

Methyl aminolevulinic acid cream (MAL)

• used for the treatment of Actinic KeratosesActinic Keratoses are collections of abnormal skin cells found in the upper layers of skin that develop after prolonged exposure to sun light. AKs are precancerous lesions. Click here for more information. and superficial Basal Cell CarcinomaBCC is the most common form of skin cancer, accounting for 75% of all skin cancers. Click here for more information.
• used with red light
• cutaneous photosensitvity resolves within 24 hours after application

Aminolevulinic acid (ALA) hydrochloride topical solution

• commonly used for the treatment of Actinic KeratosesActinic Keratoses are collections of abnormal skin cells found in the upper layers of skin that develop after prolonged exposure to sun light. AKs are precancerous lesions. Click here for more information.
• used with blue light

Porfimer sodium

• administered intravenously
• causes generalised cutaneous photosenstivity that can last for months.
• research purposes only.

Benzoporphyrin derivative monacid ring A

• second-generation photosensitisers not used clinically, still under evaluation.

Mechanism of action

Most cells in the body will convert ALA and MAL to protoporphyrin IX.  Protoporphyrin IX accumulates in the epidermis and sebaceous glands but accumulates more in cancer cells than in normal cells.

Light at wavelengths 405-420nm (blue light) or 635nm (red light) is most highly absorbed by (proto)porphyrins.  Following exposure to red or blue light, protoporphyrin IX expressed in the skin (dermis) is excited to a higher energy state. The transfer of energy to oxygen under these circumstances generates reactive oxygen species which induces cell death. The reactive oxygen species are localized to the cancer cells selectively destroying them and not the surrounding normal tissue. 

Light sources for ALA and MAL

Light sources used in PDT include laser or light at other frequencies with suitable spectral characteristics. Laser light is suitable for small skin lesions whilst other light sources may be better for the treatment of large skin lesions as the field of illumination is larger. Blue light is generally most effective when used with ALA whilst red light is usually used with MAL.  

PDT administration (topical)

Phase 1

• photosensitising drug is applied to the lesion.
• gentle scraping of the lesion is often performed to allow better absorption of the photosensitiser into the desired area.
• a certain period of time is waited to allow the drug to concentrate in the cancer cells.

Phase 2

• a light source with the appropriate wavelength is shone directly on to the treated area.
• treatment usually last 5-45 minutes.
• sometimes a 2nd cycle of treatment may be given 1-2 weeks later.

Phase 3

• a phototoxic reaction will occur, and usually the wound or lesion heals within 1-2 months.

PDT in dermatology

PDT is currently being used or investigated as a treatment for the following skin conditions:

• Actinic KeratosesActinic Keratoses are collections of abnormal skin cells found in the upper layers of skin that develop after prolonged exposure to sun light. AKs are precancerous lesions. Click here for more information. (AK) or Solar Keratoses (SK) on the face and scalp
• Squamous Cell CarcinomaSquamous Cell Carcinoma (SCC) is a malignant tumour of the skin. Invasive SCC indicates that the cancer cells have grown into the deeper layers of the skin (dermis), whereas the term in-situ SCC indicate that the cancer cells remain in the upper layers of the skin (epidermis). SCC is a very common form of skin cancer. Click here for more information. (SCC, including Bowen's disease)
• Basal Cell Carcinomas (BCC)
• AcneAcne is an inflammatory disease of the skin, caused by clogged sebaceous glands which result in pimples/pustules, extremely common in adolescence. Click here for more information vulgaris
• Mycosis fungoides (cutaneous T-cell lymphoma)
• Kaposi sarcoma
• PsoriasisPsoriasis is a lifelong, non-contagious skin disease, characterised by patches of red skin covered in silver scales. Click here for more information.
• Viral warts

Adverse effects and contraindications

Photosensitivity

Photosensitivity from PDT is due to the treated area being sensitised to light.  Side effects may include:

• Pain
• Burning/stinging sensation
• Itchiness

These sensations usually decrease rapidly once the light source is paused or exposure is terminated.  A local anaesthetic may be applied to the treated area before or during PDT to help relieve pain. The photosensitivity usually lasts about 24 hours (depending on the specific agent when applied systemically. Light treatment of locally applied photosensitizer will exhaust the photosensitization.).

Phototoxicity

The phototoxic reaction on treated skin lesions is characterized by:

• Pain
• Burning/stinging
• Itchiness
• Swelling and redness
• Crusting
• Peeling and blisters

These side effects are considered as normally expected and desirable reactions to achieve clearance of the treated skin lesions, as the side effects represent death of the cancer cells.

The severity of this phototoxic reaction is variable and can sometimes be severe and associated with prolonged pain, crusting, vesicles, and intense peeling and rarely secondary infection. The phototoxic reaction is worsened when patients expose themselves to the sun or to powerful artificial light sources after PDT treatment. It is mandatory that the treated area is protected from light exposure by using a dressing for at least 48 hours following systemic application of ALA and MAL. Light treatment of locally applied photosensitizer will exhaust the photosensitization.

Although photosensitizing drugs concentrate in cancer cells, they can also make normal tissue (healthy cells) more sensitive to ambient and light sources. Photosensitizing creams may be used at the localised treatment site to reduce some of the phototoxic reactions. It is more of a problem when photosensitizing drugs are given orally or administered intravenously. These patients may find their entire body sensitive to light and should take precautions to protect themselves from light for the necessary period of time – which may be days or weeks depending on the photosensitizing drug used.

In general, treated areas may take several weeks to heal. Scarring is generally minimal (but can be moderate).

Pigmentary and hypersensitivity reactions

Hyperpigmentation (increase in pigmentation) is sometimes seen after PDT. It tends to fade over a few months. Hypopigmentation (loss of pigmentation) at treated sites has also been reported. Cases of allergic contact dermatitis and urticaria to MAL have been reported.

Introduction 

Photodynamic therapy (PDT) is a new procedure being used by dermatologists to treat certain types of malignant and benign skin conditions. It involves the use of a photosensitizing agent, oxygen and light to create a photochemical reaction that selectively destroys a desired target. The photochemical reaction that occurs, results in the formation of reactive oxygen species which mediate cytotoxic effects. In dermatology, PDT is approved for the treatment of Actinic Keratosis (AK), Bowen’s disease, Basal Cell Carcinoma (BCC) and superficial Squamous Cell Carcinoma (SCC). It appears to be as effective as conventional treatments such as cryotherapy (liquid nitrogen), curettage, radiotherapy and topical 5-fluorouracil (Efudix™ cream).

Photosensitizing agents  

The photosensitizers used for PDT are either 5-aminolevulinic acid (ALA) or its methyl ester (MAL). They are applied topically to the area to be treated.

These compounds are ideal for photosensitization because they:

1.    Are effective after topical application.

2.    Have significant light absorption at wavelengths that penetrate the skin sufficiently deep.

3.    Display tissue selectivity

4.    Have a high yield of reactive oxygen species.

Systemic photosensitizers for PDT are in trial phases but are not used clinically.

Both ALA and MAL are approved in several countries for the treatment of AKs, and in some countries for the treatment of Bowen’s disease and BCC. However it is commonly employed for other uses including the treatment of photoaging and acne vulgaris. Listed below are several photosensitising agents.

Mechanism of action  

ALA and MAL are intermediates in the heme-porphyrin pathway. Most cells of the human body can transform ALA or MAL into porphyrins specifically protoporphyrin IX.

Significant differences exist in porphyrin accumulation between various tissues and cell types. After the application of MAL or ALA to human skin, porphyrins accumulate mostly in sebaceous glands and the epidermis.

ALA and MAL selectively accumulate in epidermal tumors, which is demonstrated by the ratio of porphyrin induction in tumors to the surrounding skin higher than 10:1. This preponderance to accumulate within malignant cells is thought to be related to altered metabolism and also enhanced ALA/MAL penetration through an abnormal stratum corneum.

Light at a wavelength corresponding to a peak of the porphyrin excitation spectrum in tissues is used to most efficiently generate a therapeutic effect. 405-420 nm is the most important excitation peak of protoporphyrin IX and is corresponds to blue light which is used with ALA. Another peak in the excitation spectrum of porphyrins includes a red peak at approximately 635 nm and is often used with MAL.

Following blue or red light irradiation protoporphyrin IX absorbs light and is converted to an excited higher energy triplet state. When this energy is transferred to oxygen, reactive oxygen species are generated such as singlet oxygen or free radicals. The generation of singlet oxygen species labeled a type 2 photochemical reactions, are believed to predominate in PDT.

Singlet oxygen species are toxic to cells. Biologic effects may be primary, cellular or secondary, vascular damage. Cellular effects include apoptosis or necrosis of intra-cellular organelles such as mitochondria or lysosomes. Vascular damage is a result of vasoconstriction, thrombosis, ischemia and subsequent necrosis of the vessels associated with the target. Direct cellular damage is the usual mechanism of action when the photosensitiser is applied topically.

PDT with various photosensitizers has been shown to modify cytokine expression and induce immune-specific responses. Immunologic effects include the production of interleukin 1-beta, interleukin 2, tumor necrosis factor-alpha, and granulocyte colony-stimulating factor. PDT generally has a low potential for causing DNA damage, mutations, and carcinogenesis.

Light sources for ALA and MAL 

Light sources used in PDT include laser or nonlaser light with suitable spectral characteristics.  Laser light has the advantages of being:

• monochromatic (exactly one colour/wavelength that corresponds with the peak absorption of the photosensitising agent)
• coherent (able to focus lightwaves to specific site)
• intense (high irradiance allowing for shorter treatment times)

Laser light is suitable for small skin lesions whilst non-laser light is better for the treatment of large skin lesions as the field of illumination is larger.

PDT administration (topical) 

PDT is a 3-step procedure 

In the first step the photosensitising drug is applied to the lesion. A period of time is waited, usually between 30min-3 hrs, to allow the drug to concentrate in the target cells. The skin may be gently scraped (curretage) beforehand to increase the amount of the drug absorbed.

The second step involves activation of the photosensitizer in the presence of oxygen with a specific wavelength of light directed toward the target tissue. Treatment usually lasts between 5-45 minutes. Depending on the type of lesion being treated and the photosensitizing chemical used, a second treatment may be required.

A sunburn reaction develops, which is the third stage, and represents the cytotoxic damage to cells. This usually heals within 4-8 weeks.

Because the light source is directly targeted on the lesional tissue and the photosensitizing drug is preferentially absorbed by malignant cells, PDT achieves dual selectivity, minimizing damage to adjacent skin.

PDT in dermatology 

PDT is currently being used or investigated as a treatment for the following skin conditions:

• Actinic Keratoses (AK) or Solar Keratoses (SK) on the face and scalp
• Squamous Cell Carcinoma (SCC, including Bowen's disease)
• Basal Cell Carcinoma (BCC)
• Acne Vulgaris
• Mycosis fungoides (cutaneous T-cell lymphoma)
• Kaposi sarcoma
• Psoriasis
• Viral warts   

Adverse effects 

Photosensitivity 

Photosensitivity from PDT is due to the treated area being sensitised to light. Side effects may include a burning sensation or pruritus during light exposure after ALA or MAL application. These sensations usually decrease rapidly once the light source is paused or exposure is terminated. A local anaesthetic may be applied to the treatment area before or during Stage 2 of the procedure to help relieve pain.

Photosensitivity usually lasts about 24 hours depending on the specific agent.  Light treatment of locally applied photosensitizer will exhaust the photosensitization.

Phototoxicity  

The phototoxic reaction on treated skin lesions is characterized by erythema, edema, crusting, vesicles, or erosion in most patients. This is considered a normal and desirable reaction to achieve clearance of these lesions.

The severity of this phototoxic reaction is variable and can sometimes be severe and associated with a burning sensation, pain, crusting, vesicles, and intense peeling.

This phototoxic reaction is greatly enhanced and can be quite severe if patients expose themselves to the sun or to powerful artificial lights after treatment. The treated area should be protected from light exposure using a dressing for at least 48 hours following topical application of ALA and MAL and possibly longer with systemic photosensitizing agents. Light treatment of locally applied photosensitizer will exhaust the photosensitization.

Concurrent use of topical retinoids has been reported to significantly increase phototoxicity.

Although photosensitising drugs concentrate in cancer cells, they can also make healthy cells more sensitive to light. This is not a problem when photosensitising creams (ALA, MAL) are used as they are localised to the treatment site. It is more of a problem when photosensitising drugs are given by mouth or injected intravenously. These patients may find all parts of their body sensitive to light and should take precautions to protect themselves from light for the necessary period of time which may be days or weeks depending on the photosensitising drug used.

Treated areas take several weeks to heal. Scarring is generally minimal (but can be moderate). 

Pigmentary abnormalities  

Hyperpigmentation is sometimes seen after PDT. It tends to fade over a few months. Hypopigmentation at treated sites has also been reported.

Hypersensitivity reactions  

Cases of allergic contact dermatitis and urticaria to MAL have been reported.

Limitations

PDT is unable to assure complete eradication of malignancy as there is no histological specimen that can be assessed.

Contraindications 

PDT can be contraindicated in patients with cutaneous sensitivity at 400-450 nm, porphyria or known allergies to porphyrins. In addition, caution should be used in patients sensitive to other wavelengths, given that some clinicians are using ALA with a light source outside the 400- to 450-nm range.

PDT has not been trialed in pregnancy or in children.

References

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• Goldberg, J (2008). Laser Dermatology. Blackwell Publishing, Oxford.
• Kendall, C A & Morton, C A (2003). 'Photodynamic Therapy for the Treatment of Skin Disease'. Technology in Cancer Reseatch & Treatment. Vol 2 (4), pp283-288.
• Krutmann, J & Elmets, C A (1995). Photoimmunology. Blackwell Publishing, Boston, 1995.
  
• Sakamoto, F H, Wall, T, Avram, M M, Anderson, R R (2008). 'Lasers and Flashlamps in Dermatology', In: Wolff, K, Goldsmith, L A, Katz, S I, Gilchrest, B A, Paller, A S & Leffell, D J (2008). Fitzpatrick’s Dermatology in General Medicine, McGraw-Hill.
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