Photodynamic Therapy (PDT) and Phototoxicity

Snapshot

Other common terms: PDT photosensitivity/light sensitivity, drug induced phototoxicity

ICD-10 classification: L56.0 (drug induced photosensitivity)

Prevalence: Common dermatological treatment. Systemic PDT treatment is still considered a novel therapy for many indications.

Causes: Phototoxicity is bought on by administration of a photosensitizing drug

Symptoms: Phototoxicity: swelling, burning, itching and redness of the skin, occurring during or after exposure to sunlight, including light passing through windows.

Treatments/cures: Phototoxicity can be avoided by complete avoidance of sunlight and certain artificial lights.

Photodynamic therapy (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.

Systemic photodynamic therapy
Systemic photodynamic therapy

Photosensitizing 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. One side effect of systemic PDT is phototoxicity and photosensitivity in patients’ skin for up to three months following treatment, dependent upon the photosensitizing drug used.

Current evidence is showing PDT to be effective in treating Actinic Keratoses (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

Operation room
Operation room

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.

These compounds are ideal for photosensitization because they:

  • Are effective after topical application.
  • Have significant light absorption at wavelengths that penetrate the skin sufficiently deep.
  • Display tissue selectivity
  • 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 photosensitizing agents.

Photosensitizing agents

Methyl aminolevulinic acid cream (MAL)

  • used for the treatment of Actinic Keratoses and superficial Basal Cell Carcinoma
  • 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 keratoses
  • used with blue light

Porfimer sodium

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

Benzoporphyrin derivative monacid ring A

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

Mechanism of action

Most cells in the body will convert ALA and MAL to protoporphyrin IX (PPIX), a chemical (specifically, a porphyrin) which occurs naturally in the haem synthesis pathway and is responsible for phototoxicity in erythropoietic protoporphyria (EPP).

After the application of MAL or ALA to human skin, porphyrins accumulate mostly in sebaceous glands and the epidermis but tend to accumulate more in cancerous cells than in normal cells.

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.

Argon Ion Laser
Argon Ion Laser

Light at wavelengths 405-420nm (blue light) or 635nm (red light) is most highly absorbed by (proto)porphyrins, known as their peak excitation spectrum. 405-420nm is the most important peak in the excitation spectrum and is used in ALA. 635nm is a secondary peak and is often used with MAL.

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 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 (cell death) 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 photosensitizer is applied topically.

The reactive oxygen species are localized to the cancer cells selectively destroying them and not the surrounding normal tissue.

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 light at other frequencies with suitable spectral characteristics.

Laser light has the advantages of being:

  • monochromatic (exactly one colour/wavelength that corresponds with the peak absorption of the photosensitizing 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.

Blue light is generally most effective when used with ALA whilst red light is usually used with MAL.

PDT administration (topical)

Photofrin is a photosensitizer used in photodynamic therapy
Photofrin is a photosensitizer used in photodynamic therapy

PDT is a 3-step procedure.

In the first step the photosensitizing 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.

 

Phase 1

  • photosensitizing drug is applied to the lesion.
  • gentle scraping of the lesion is often performed to allow better absorption of the photosensitizer 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 keratoses (AK) or solar keratoses (SK) on the face and scalp
  • Squamous cell carcinoma skin cancer (SCC, including Bowen's disease)
  • Basal cell carcinoma skin cancer (BCC)
  • Acne vulgaris
  • Mycosis fungoides (cutaneous T-cell lymphoma)
  • Kaposi sarcoma
  • Psoriasis
  • Viral warts

Photodynamic therapy side effects

PDT treatment can cause serious side effects, dependent upon the method of treatment and the photosensitizing drugs being used.

Photosensitivity

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

  • Pain
  • Burning/stinging sensation
  • Itchiness (pruritis)

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 (pruritis)
  • Swelling and redness (erythema)
  • 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 if 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. In systemic PDT, patients should remain away from light for up to three months following treatment. Light treatment of locally applied photosensitizer will exhaust the photosensitization. Concurrent use of topical retinoids has been reported to significantly increase phototoxicity.

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.

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

  • Altshuler, G B et al (2001). 'Extended theory of selective photothermolysis.' Laser surg Med. Vol 29 (5), pp416-432.
  • Burkhardt, B R & Maw, R (1997). 'Are more passes better: Safety versus efficacy with the pulsed CO2 laser.' Plast Reconstr Surg. 100 (6), pp1531-1534.
  • Fritsch, C, Goerz, G & Ruzicka, T (1998). 'Photodynamic Therapy in Dermatology.' Archives of Dermatology , Volume 134.
  • 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.
  • Sriprachya-Anunt S et al (1997). 'Infections complicating pulsed carbon dioxide laser resurfacing for photoaged skin.' Dermatol Surg. Vol 23 (7), pp527-535.
  • Zenzie HH et al (2000). 'Evaluation of cooling methods for laser dermatology.' Lasers Surg Med Vol 26 (2), pp130-144.

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