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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
Porfimer sodium 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.

Associations online

Snapshot
Other common terms: VZV, chickenpox (varicella), shingles (herpes zoster)
ICD-10 classification: B01, B02
Prevalence: Very common with up to 1,500:100,000 reported.
Causes: Airborne transmission
Symptoms: Incubation period (2 weeks): fever, general malaise, abdominal pain, headache. Followed by skin lesions; a rash which eventually crust and heal.
Treatments/cures: No known cure. Treatment is generally avoided except in extreme cases. Relief of rash is mainstay of treatment.
Skin lesion (chickenpox) from VZV infection
Skin lesion (chickenpox) from VZV infection
The varicella zoster virus (VZV) is the cause of chickenpox (varicella), and shingles (herpes zoster). Varicella occurs as the primary infection, more commonly in childhood but can occur in adulthood. Herpes zoster is a result of reactivation of latent infection of nerve ganglia. The rate of infection is currently trending downwards with the introduction of a varicella zoster virus vaccine. Prognosis of the primary infection is generally good except in some instances. Patients who acquire the infection in adulthood have a higher mortality risk. Patients who are immunocompromised are also at risk. A developing foetus may acquire congenital problems if a primary infection occurs during pregnancy. Neonatal infections may also result in chronic complications.

Incidence

VZV infection was quite common prior to the introduction of the vaccine in 1995. Incidence rates of 1,500-1,600 per 100,000 have been reported in the USA. Since the introduction of the vaccine, reported incidence rates have markedly decreased. Where varicella was the principal problem, the hospitalization rate was 2.3-6.3: 100,000. The case-fatality rate was reported as 0.8 per 100,000 in children aged 1-4 years, and 21.3 per 100,000 in adults aged more than 20 years. A separate series reports a mortality rate of 9.22 per 100,000 consultations related to varicella. However, adults accounted for 81% of deaths despite representing only 19% of consultations. The majority of primary infections occur in children. While adults are less likely to acquire varicella, adults who do acquire the infection have a higher mortality rate. Current post-vaccine surveillance data is available from the Department of Health and Ageing (with the exception of the Australian Capital Territory, Victoria, and New South Wales). A total of 1,514 cases of varicella were reported in 2006. The highest incidence rates of varicella were 93.4:100,000 in the Northern Territory, and 48.9:100,000 in South Australia (Department of Health and Ageing, 2006). The highest incidence occurred in children aged 0-4 years (120:100,000). The overall Australian incidence was not available. A total of 1,052 cases of herpes zoster were reported in the same year. The overall rate was 5.2:100,000. Similarly, the highest rates were in South Australia (40.2: 100,000) and Northern Territory (38.7:100,000) (Department of Health and Ageing, 2006). Surveillance data prior to the introduction of the varicella vaccine in Australia is unavailable.

Causes

Skin lesion (chickenpox) from VZV infection
Skin lesion (chickenpox) from VZV infection
The main route of VZV infection is airborne transmission. In addition, direct contact may also transmit the virus. Unfortunately, even without the characteristic skin problems, a patient can still produce and spread the virus. The prodrome of varicella (non-specific symptoms such as fever and general malaise) gives little clue as to the proceeding illness. As such, preventing transmission can be difficult. Herpes zoster is a reactivation of latent VZV infection. The risk of reactivation increases with age. In addition, reactivation is associated with immune compromise. HIV infection, bone marrow disease, or immune-suppressing medications may all predispose to reactivation and severe complications. However, reactivation may also occur randomly with no discernible cause. VZV belongs to the family of herpesviruses and specifically the alphaherpesviruses. Their genome consists of double-stranded deoxyribonucleic acid (DNA) within an icosahedral nucleocapsid. The outermost layer is a lipid membrane. This confers a susceptibility to environmental factors such as heat, and detergents or solvents. Transmission between hosts usually occurs via inhalation of aerosols containing varicella zoster virus. Transmission via direct contact is less frequent but may also occur. VZV is hypothesized to be spread via leukocytes in the lymphatic system. People with obvious varicella are advised to remain at home to minimize spread of the virus. It is advised that patients not attend their usual occupation until a crust has formed over the initial lesions. Virus shedding is minimized once this has occurred. The virions first spread to local lymph nodes, where a primary viraemia occurs. The virus then infects other leukocytes and hepatocytes before producing a secondary viraemia to infect mucous membranes and skin epithelia. The time up to this point is considered to be the incubation period, which lasts approximately 14 days. Infection of the skin epithelia results in the characteristic lesions seen in varicella. Transmission of the virus is actually possible before the onset of these lesions. Following this, the virus forms a latent infection within nerve ganglia. Viral replication occurs within host cells. The virus binds to proteins on the surface of cells which induces its entry into host cells; the receptors used by VZV to facilitate cellular entry have not been identified. The host’s cellular mechanisms are then utilized to reproduce new viruses. Both humoral and cellular immunity is important in containing the infection. In immunocompromised patients, severe complications of VZV are more likely to occur

Symptoms

Skin lesion (shingles) from VZV infection
Skin lesion (shingles) from VZV infection
The incubation period of VZV is approximately 14 days, during which the patient may experience a number of non-specific symptoms such as:
  • Fever
  • General malaise
  • Abdominal pain
  • Headache
Following these symptoms, the characteristic skin lesions evolve, beginning with a macular rash, progressing to vesicles, which rupture and form hard crusts that eventually heal. Ulcerated lesions are often painful. These lesions typically develop around the entire body, but are concentrated centrally on the trunk. Lymphadenopathy is also seen. These lesions occur throughout the body, but are more concentrated around the trunk than the limbs. While this pattern is suggestive of varicella, abnormal distributions may occur. Complications of varicella include secondary bacterial infection, transient hepatitis, respiratory and neurological involvement, haemorrhagic complications, and nephritis. Congenital varicella syndrome may also occur. Patients with neurological complications may have cerebral signs, cerebellar signs, or a combination of both. Signs of meningitis such as photophobia, headache, and neck stiffness may also occur. Congenital varicella syndrome is characterized by microcephaly, limb hypoplasia, cutaneous defects, hypopigmented skin, and autonomic neuropathy. Herpes zoster: The skin lesions that occur in herpes zoster are similar to those in varicella. However, because reactivation of the virus typically occurs from one particular ganglion, the lesions occur in the distribution of a specific dermatome. The typical prodromal symptoms of fever and general tiredness may or may not be evident. However, pain in the same distribution as the skin lesions is likely, and may last even after the lesions have healed. Complications of herpes zoster include postherpetic neuralgia, and neurological involvement. Approximately 9% of patient with herpes zoster develop postherpetic neuralgia, which is characterised by pain persisting for long periods of time despite resolution of skin lesions. Only 0.2-0.5% of patients have neurological involvement; the majority recover without permanent impairment.

Treatments

Treatment for VZV infection is generally not required. However, guanosine analogues (such as acyclovir) are available. These are generally used in certain cases such as in immunocompromised patients, or in patients in whom severe infection or complications have developed. Passive immunization is also available. Immunoglobulin (antibodies) against VZV is administered to patients who are at risk of developing serious complications. This immunoglobulin is pre-formed and thus works even for immunocompromised patients. Treatment of immunocompromised adults with varicella with acyclovir does not improve skin healing rates, but can significantly reduced visceral complications. Acyclovir 10mg/kg for 7-10 days has been recommended. Administration via intravenous route over eight hours is preferred. The mainstay of treatment for VZV infection is prevention. A live attenuated vaccine was introduced in 1995. This vaccine has markedly reduced the rate of varicella. In addition, complication and mortality rates have also decreased. A similar vaccine is also available to prevent herpes zoster. Treatment is required for all patients with herpes zoster. The following regimens are recommended by Therapeutic Guidelines Ltd. (2004):
Drug Dose (oral) Frequency (Duration of 7 days)
Acyclovir 20mg/kg for children Five times daily
Acyclovir 800mg for adults Five times daily
Famiciclovir 250mg 8 hourly
Valacylovir 1000mg 8 hourly

Prevention

Individuals at high risk (e.g. pregnant women, immunocompromised individuals) should avoid patients with active disease. Children who acquired varicella should stay at home until the skin lesions have healed or crusted.

Vaccination

Active immunization:

Skin lesion (chickenpox) from VZV infection
Skin lesion (chickenpox) from VZV infection
A live-attenuated vaccine for the prevention of varicella is currently available. This vaccine works by mimicking a viral infection; the strain used is not as virulent, and does do not cause disease readily. The body is still able to recognize the foreign components of the virus, and develop an immune response and long term immunity against it. In Australia, it is recommended that newborns receive the vaccine between the ages of 12-15 months, followed by a second immunization at 4-6 years. Older children and adults who have not received the vaccine and have not previously been infected are advised to obtain the vaccine, unless there is a specific contraindication. The vaccine is available for free in Australia for those who fit the eligibility criteria (Department of Health and Ageing, 2008):
  • All children born on or after 1 May 2004 at 18 months of age
  • A one year cohort of children aged between 10 and 13 years who have not received varicella vaccine and who have not had the disease – commencement date and specific age group varies between States and Territories
The vaccine has been reported by Seward et al. (2002) to reduce mortality rates in America from 2.7-4.2:100,000 to 0.6-1.5:100,000. Other authors also support the cost-effectives of providing vaccination during infancy (Scuffham et al., 1999). Contraindications to the varicella vaccine include (Zimmerman, 1996):
  • Immuno-compromised individuals – Patients with HIV infection – Patients undergoing immunosuppressive therapy (such as high dose corticosteroid) – Patients with congenital immune deficiencies
  • Individuals with a history of anaphylaxis
  • Pregnancy
  • Untreated tuberculosis
A similar vaccine is also available for prevention of herpes zoster (reactivation of latent VZV). This vaccine is similar to the varicella vaccine, but has a higher dose of live virus. It has been shown to reduce reactivation of latent VZV (Holcomb & Weinberg, 2006). Where reactivation occurs, the rate of post-herpetic neuralgia was reduced. In addition to the contraindications listed above for the varicella vaccine, the herpes zoster vaccine should not be given to children as it has a higher viral load.

Passive immunization:

Administration of intravenous immunoglobulin against VZV is sometimes used for immunocompromised patients who have been exposed to VZV. Active immunization (i.e. live attenuated vaccine) is contraindicated in these cases as the patient would be unable to mount an adequate immune response, and may in fact develop an infection instead.

Prognosis

The mortality and morbidity rates of VZV infection have been significantly reduced since the introduction of the live attenuated vaccine in 1995. However, significant complications may still occur. Primary infection in adulthood holds a poorer prognosis than childhood infection. Higher mortality rates have been reported (Rawson, 2001). Data on the rate of severe complications is limited. A German study estimated severe complications to occur at 8.5 per 100,000 cases (Ziebold et al., 2001). Of 119 cases in the study, neurologic complications occurred in 73 children (61.3%), infectious complications occurred in 46 children (38.6%). Only eight patients reported long term complications; six due to infectious causes, and two due to neurologic complications (Ziebold et al., 2001). Immunocompromised patients have much poorer prognosis. The rate of developing congenital varicella syndrome is low. In a cohort of 362 women (15 with herpes zoster, and 347 with primary VZV infection), only one case of definite congenital varicella and two foetal deaths were documented (Harger et al., 2002). The incidence of herpes zoster increases with age. Incidence ranges from 4.2 per 1,000 person-years (age group 50-59) to 10.7 per 1,000 person-years (age group ?80) (Yawn et al., 2007). The most common complication of herpes zoster is associated pain and post-herpetic neuralgia. On average, 18% of patients may experience pain for more than 30 days. Again, this proportion increases with age Yawn et al., 2007). Other complications include ocular complications (4%), and neurological complications (3%). Less than 1% develop disseminated infection (Yawn et al., 2007).

References

  • Arvin, A M (1996). ‘Varicella-zoster virus’. Clinical microbiology reviews, 9(3), 361-381. Available online.[Accessed on 9/12/2008].
  • Balfour, H H Jr, McMonigal, K A & Bean, B (1983). ‘Acyclovir therapy of varicella-zoster virus infections in immunocompromised patients’. Journal of Antimicrobial Chemotherapy, 12(B), 169-179. Abstract available online [Accessed on 9/12/2008].
  • Department of Health and Ageing (2006). Australia’s notifiable diseases status, 2006: Annual report of the National Notifiable Diseases Surveillance System – Results: Vaccine preventable diseases. Communicable Diseases Intelligence, 3(2). Available online. [Accessed on 9/12/2008].
  • Department of Health and Ageing (2008). Varicella (chickenpox) vaccination program – common questions & answers for providers [Online]. [Accessed on 9/12/2008, no longer online].
  • Harger, J H, et al. (2002). ‘Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women.’ Obstetrics & Gynecology, 100, 260-265. Available online. [Accessed on 9/12/2008. Link no longer active.].
  • Holcomb, K & Weinberg, J M (2006). ‘A novel vaccine (Zostavax) to prevent herpes zoster and postherpetic neuralgia’. Journal of Drugs in Dermatology, 5(9), 863-866. Abstract available online. [Accessed on 10/12/2008].
  • Marin, M, Meissner, H C & Seward, J F (2008). ‘Varicella prevention in the United States: A review of successes and challenges’. Pediatrics, 122(3), 744-751. Available online. [Accessed on 9/12/2008].
  • Rawson, H, Crampin, A & Noah, N (2001). ‘Deaths from chickenpox in England and Wales 1995-7: Analysis of routine mortality data.’ British Medical Journal, 323, 1091-1093. Abstract available online. [Accessed on 9/11/2008].
  • Scuffham, P A, Lowin, A V & Burgess, M A (1999). ‘The cost-effectiveness of varicella vaccine programs for Australia’. Vaccine, 18(5-6), 407-415. Abstract available online [Accessed on 9/12/2008].
  • Seward, J F, Watson, B M, Peterson, C L, Mascola, L, Pelosi, J W & Zhang, J X (2002). ‘Varicella disease after introduction of varicella vaccine in the United States, 1995-2000’. Journal of the American Medical Association, 287(5), 606-611. Abstract available online. [Accessed on 9/11/2008].
  • Spear, P G & Straus, S E (2007). ‘Alphaherpesviruses: Herpex simple virus and varicella-zoster virus’. Schaecter’s Mechanisms of Microbial Disease. 406-414. Lippincott Williams & Wilkins.
  • Therapeutic Guidelines Ltd. (2004). Infectious diseases. Therapeutic Guidelines: Dermatology 2nd Edition. 201-220. Therapeutic Guidelines Limited.
  • Yawn, B P, Saddier, P, Wollan, P C, StSauver, J L, Kurland, M J & Sy, L S (2007). ‘A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction’. Mayo Clinic Proceedings, 82, 1341-1349. [Accessed on 10/12/2008]
  • Ziebold, C, von Kries, R, Lang, R, Weigl, J & Schmitt, H J (2001). ‘Severe complications of varicella in previously healthy children in Germany: A 1-year survey’. Pediatrics, 108(5), e79. Available online. [Accessed on 10/12/2008]
  • Zimmerman, R K (1996). ‘Varicella vaccine: Rationale and indications for use’. American Family Physician [Online]. [Accessed on 10/12/2008, no longer online].

Online resources

Better Health Channel, Victoria:

Online associations

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.

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).

Systemic photodynamic therapy

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.

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

Operation room

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

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)

Porfimer sodium 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
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