Adverse Effects of Topical Photodynamic Therapy

A Consensus Review and Approach to Management

S.H. Ibbotson; T.H. Wong; C.A. Morton; N.J. Collier; A. Haylett; K.E. McKenna; R. Mallipeddi; H. Moseley; L.E. Rhodes; D.C. Seukeran; K.A. Ward; M.F. Mohd Mustapa; L.S. Exton

Disclosures

The British Journal of Dermatology. 2019;180(4):715-729. 

In This Article

Phototoxicity of Topical Photodynamic Therapy

The inflammatory reaction following PDT is expected as a consequence of the phototoxic effect. This usually manifests as erythema and oedema, and sometimes with associated wheal and flare, i.e. an urticarial reaction.[116,117] Persistence of erythema may be seen for some months after treatment.[11] Crusting, infection, sterile pustules and erosions are also uncommon adverse effects.[118]

In a study involving 10 healthy volunteers, erythema induced by ALA-PDT peaked at 1–2 h after stopping irradiation,[6] although laser Doppler studies have shown that the increase in blood flow that occurs immediately after topical PDT persists for a week.[119] Marked interindividual variability is seen in phototoxic reaction and there are also body sites effects, with reports of increased phototoxic reactions mid-face,[120] consistent with increased pain at this site.[22] Phototoxic inflammation seems to be greater following the application of ALA rather than MAL. In a randomized comparison of ALA-PDT and MAL-PDT involving 34 healthy volunteers, a composite score of erythema, oedema and pigmentation was significantly greater for ALA-PDT than for MAL-PDT, which likely reflected the increased pigmentation seen with ALA-PDT, persisting for 4 weeks.[43]

Detailed investigation of ALA-PDT-induced phototoxicity in normal human skin indicated the release of histamine, accompanying an early urticarial phase, although cetirizine showed no effect on the erythemal response at 24 h.[4] Consistent with this is the occurrence of clinically reported urticaria seen immediately, during and after topical PDT in a small proportion of patients, and possibly being more likely in those with severe photodamage. The incidence of urticaria has been reported to be between 0·9% and 3·8%, and antihistamines may be of some benefit when used prophylactically for itch and wheal.[121,122] Prominent phototoxic erythema, associated with malaise and flu-like symptoms, was recently reported in two organ transplant recipients treated with PDT for photodamage.[123]

While there is significant evidence of an association between prodrug-induced fluorescence, phototoxicity and pain,[21,38,124,125] an association between phototoxicity and therapeutic outcome is less clear cut. An association between PpIX photobleaching and clinical outcome at the 3-month follow-up after PDT treatment was observed in a pilot study in diseased skin.[126] In a separate study involving 24 healthy volunteers, forearm skin was tape-stripped and during different times of incubation of MAL, fluorescence photobleaching was assessed during red light irradiation. A significant correlation was seen between the incubation time of the prodrug and time to illumination and photobleaching; there was also a significant correlation between photobleaching and erythema, and between photobleaching and pain. These imply that shorter incubation periods of the prodrug may result in reduced pain, although impact on efficacy in diseased skin is unclear.[127] In addition, reduced MAL concentration may also reduce any potential for increased pigmentation.[128]

In a study of 22 patients with field change mild AK on the face and scalp, the application of MAL for 30 min vs MAL for 3 h, with both sites then irradiated at 3 h, was investigated. The application of a super-potent corticosteroid before and after PDT to the short application, pulsed PDT site was also investigated. The reduction of MAL application time and the use of topical corticosteroid reduced PDT-induced erythema at 24 h but did not impact on efficacy at 3 months.[129] The same group studied 22 patients with facial and scalp AK separately and also showed that application of a super-potent corticosteroid reduced the inflammation and erythema of PDT but did not impair efficacy.[130] Furthermore, during dPDT, using light protection of the skin following PDT appears to reduce inflammation, although its impact on efficacy is unclear.[131] It is also of interest to note that brimonidine tartrate gel may also have the potential to reduce erythema after dPDT, although its impact on efficacy, again, is unknown.[132]

Patient Satisfaction, Tolerance and Cosmetic Outcome

High levels of patient satisfaction are reported for PDT, although pain may impact on patients' perception of the treatment.[78,79,88,92,133–139] Improved tolerance and satisfaction with PDT was reported in one randomized study comparing PDT with imiquimod for AK.[140–142] Improved preference for PDT compared with cryotherapy was reported in a RCT, with a 5-year follow-up, comparing MAL-PDT with cryotherapy for superficial BCC.[88] MAL-PDT compares favourably with ingenol mebutate when used for AKs on the face and scalp, with superior cosmetic outcomes and an overall patient preference for PDT, owing to higher pain scores and local skin reactions being more severe and persistent with ingenol mebutate.[93,94] Similarly, when dPDT was compared with ingenol mebutate in 27 participants with AK in a within-patient study, the former was better tolerated and preferred, and was associated with fewer adverse effects; efficacy was similar between the two modalities.[95] When comparing trichloroacetic acid with ALA-PDT for scalp AK, higher efficacy rates and pain scores were seen with PDT and scarring was present only in those treated with trichloroacetic acid.[96]

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