10.2 Photodynamic therapy

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Background

Photodynamic therapy (PDT) involves the use of light to activate a photosensitiser that is localised in diseased tissues, resulting in the formation of cytotoxic reactive oxygen species. Light sources include high-intensity lamps, lasers and, more recently, daylight.

Topical PDT is a non-invasive treatment option for some patients with actinic keratoses (AKs), Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC), and superficial and thin basal cell carcinomas (BCCs).[1]

Each treatment session involves gentle debridement or removal of scales for AK, Bowen's disease and superficial BCC, or debulking of nodular BCC, typically without the requirement for local anaesthesia.

In conventional PDT, the photosensitising cream is then applied 1mm thick to the treatment field for AK or the lesion (plus a 5mm margin), then covered with an occlusive dressing. This preparation takes approximately 15 minutes. The cream is left in place for 3 hours, the area is then wiped clean with saline and illumination is applied for 7–9 minutes.

More recently 'daylight PDT' with the photosensitiser methyl aminolevulinate (MAL; Lumexia) was approved by the Australian Therapeutic Goods Administration (TGA) for the treatment of AK. It is used as per the current product information with daylight exposure beginning within 30 minutes of the application of the photosensitiser MAL and continuing for 2 hours.[2]

The alternative photosensitiser, 5-aminolevulinic acid (ALA), has also been investigated in PDT (ALA-PDT).

Good cosmetic results have been reported for PDT, with minimal scarring seen after most PDT treatments.[3]

For AK, the recommended regimen is a single session of PDT, with the effects assessed at 3 months.[4] Any residual lesions can, if required, then receive a second session of treatment.

For Bowen's disease and BCC, the recommended regimen is two sessions of treatment, 1 week apart, although in practice the interval between the two sessions may be up to a month.

Photodynamic therapy can be delivered in a single treatment session over large surface areas, and is therefore suitable for the treatment of patients with multiple AK.

Specialised equipment and training is required for PDT (except for daylight MAL-PDT). It is therefore primarily restricted to specialist use or use within centres specialising in skin cancer management.
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Overview of evidence (non-systematic literature review)

Actinic keratosis

There is now a large body of evidence to support the use of PDT for the treatment of AK, including four phase III randomised controlled trials (RCTs) evaluating MAL-PDT and two evaluating ALA-PDT.[3][5][6][4][7]

The complete response rate for AK at 3 months and 6 months after two treatments sessions is approximately 90%.[5][6][4][8]

Photodynamic therapy is generally well tolerated by patients.[4][7] Pain at the time of the illumination can be problematic and may require interventions such as the temporary suspension of illumination and/or the injection of local anaesthetic.[3][5][6]

The introduction of daylight MAL-PDT has enabled longer, lower intensity light delivery. This advance has largely addressed the pain issue without compromising efficacy permitting the successful field treatment for large areas of AKs, provided that supervised preparation and application protocol is followed.[3][5][6][9][10][11]

In phase III studies investigating the use of MAL-PDT in AK, the cosmetic outcome was rated as excellent or good by over 90% of investigators and patients.[3][5][6]
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Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC)

The efficacy of PDT in Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC) has been shown to be at least equal to that of cryotherapy and 5-fluorouracil, with fewer complications and superior cosmetic outcomes.[12][13][14]

A 64-month recurrence rate of 17% has been reported in Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC).[15]

Topical PDT is well suited for treatment of Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC) in slow healing sites such as the lower limb. Healing is quicker in these sites and there is less risk of the development of a non-healing ulcer or an infection compared with more destructive or surgical therapies.[13]

Cutaneous squamous cell carcinoma

While some studies have demonstrated efficacy for the use of PDT in superficial cSCC, there have been relatively high recurrence rates.

Thus, PDT cannot be recommended for the treatment of cSCC.[16][17]

Basal cell carcinoma

Longer-term (5-year) follow-up data demonstrate efficacy and good cosmetic results for PDT in the treatment of superficial BCC or nodular BCC.[18][19]

Superficial basal cell carcinoma

Prospective studies,[20][21] including RCTs, have reported 3-month clearance rates ranging from 80% to 97% for MAL-PDT in the treatment of primary superficial BCC.[20][21]

An RCT comparing PDT with cryotherapy in the treatment of superficial BCC outcomes reported no difference in 5-year recurrence rates between the two treatments (20% with cryotherapy versus 22% for MAL-PDT p=0.86). The investigators noted that the cosmetic result was excellent with MAL-PDT (60% versus 16% with cryotherapy p=0.00078).[18] A recent meta-analysis concluded PDT is an effective treatment for low-risk BCC, with excellent cosmesis and safety.[22]
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Nodular cell basal cell carcinoma

With topical PDT for nodular BCC, delivery of sufficient photosensitiser and light to the full depth of the lesion is critical to achieve cure.[21] Therefore, with the use of PDT for nodular BCCs greater than 2mm in depth, the response may be optimised by debulking the tumour prior to treatment with a curette or shave excision.[21] Re-treatments may well be necessary in these circumstances.[20][23][24][25][21]

An RCT comparing PDT with surgical excision in the treatment of nodular BCC reported 5-year clearance rates of 76% (95% confidence interval [CI] 59–87%) and 96% (95% CI 84–99%), respectively.[19] The investigators noted that PDT was associated with a more favourable cosmetic outcome than surgery.[19] A single-centre study reported that there were significantly higher estimated recurrence rates for nodular BCCs compared with superficial BCCs.[26]

Photodynamic therapy does not complicate future surgery if it is required.


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Key point(s)
  • Specialised equipment and training are required with photodynamic therapy.
  • Methyl aminolevulinate photodynamic therapy and 5-aminolevulinic acid photodynamic therapy can be considered for the treatment of actinic keratoses, Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC) and superficial basal cell carcinoma.
  • Thin nodular basal cell carcinoma can be treated with photodynamic therapy.
  • Photodynamic therapy is not recommended for invasive squamous cell carcinoma.
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References

  1. Rubel DM, Spelman L, Murrell DF, See JA, Hewitt D, Foley P, et al. Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial. Br J Dermatol 2014 Nov;171(5):1164-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24861492.
  2. Galderma Australia Pty Ltd. PI - Lumexia (methyl aminolevulinate). [homepage on the internet] Therapeutic Goods Administration; 2015 Available from: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2015-PI-01846-1.
  3. 3.03.13.23.33.4 Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, Calzavara-Pinton PG, Zane C, et al. Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study. J Am Acad Dermatol 2002 Aug;47(2):258-62 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12140473.
  4. 4.04.14.24.3 Tarstedt M, Rosdahl I, Berne B, Svanberg K, Wennberg AM. A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp. Acta Derm Venereol 2005;85(5):424-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16159735.
  5. 5.05.15.25.35.4 Pariser DM, Lowe NJ, Stewart DM, Jarratt MT, Lucky AW, Pariser RJ, et al. Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol 2003 Feb;48(2):227-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12582393.
  6. 6.06.16.26.36.4 Freeman M, Vinciullo C, Francis D, Spelman L, Nguyen R, Fergin P, et al. A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatolog Treat 2003 Jun;14(2):99-106 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12775317.
  7. 7.07.1 Piacquadio DJ, Chen DM, Farber HF, Fowler JF Jr, Glazer SD, Goodman JJ, et al. Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials. Arch Dermatol 2004 Jan;140(1):41-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14732659.
  8. Morton C, Campbell S, Gupta G, Keohane S, Lear J, Zaki I, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 2006 Nov;155(5):1029-36 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17034536.
  9. Heerfordt IM, Wulf HC. Daylight photodynamic therapy of actinic keratosis without curettage is as effective as with curettage: a randomized clinical trial. J Eur Acad Dermatol Venereol 2019 Jun 14 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/31197894.
  10. Dirschka T, Ekanayake-Bohlig S, Dominicus R, Aschoff R, Herrera-Ceballos E, Botella-Estrada R, et al. A randomized, intraindividual, non-inferiority, Phase III study comparing daylight photodynamic therapy with BF-200 ALA gel and MAL cream for the treatment of actinic keratosis. J Eur Acad Dermatol Venereol 2019 Feb;33(2):288-297 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/30022544.
  11. Lacour JP, Ulrich C, Gilaberte Y, Von Felbert V, Basset-Seguin N, Dreno B, et al. Daylight photodynamic therapy with methyl aminolevulinate cream is effective and nearly painless in treating actinic keratoses: a randomised, investigator-blinded, controlled, phase III study throughout Europe. J Eur Acad Dermatol Venereol 2015 Dec;29(12):2342-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26435363.
  12. Morton CA, Whitehurst C, Moseley H, McColl JH, Moore JV, Mackie RM. Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen's disease. Br J Dermatol 1996 Nov;135(5):766-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8977678.
  13. 13.013.1 Salim A, Leman JA, McColl JH, Chapman R, Morton CA. Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen's disease. Br J Dermatol 2003 Mar;148(3):539-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12653747.
  14. Morton C, Horn M, Leman J, Tack B, Bedane C, Tjioe M, et al. Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial. Arch Dermatol 2006 Jun;142(6):729-35 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16785375.
  15. Leman JA, Mackie RM, Morton CA. Recurrence rates following aminolaevulinic acid-photodynamic therapy for intraepidermal squamous cell carcinoma compare favourably with outcome following conventional modalities. Br J Dermatol 2002;147(Suppl 62):35.
  16. Braathen LR, Szeimies RM, Basset-Seguin N, Bissonnette R, Foley P, Pariser D, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol 2007 Jan;56(1):125-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17190630.
  17. Fink-Puches R, Soyer HP, Hofer A, Kerl H, Wolf P. Long-term follow-up and histological changes of superficial nonmelanoma skin cancers treated with topical delta-aminolevulinic acid photodynamic therapy. Arch Dermatol 1998 Jul;134(7):821-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9681345.
  18. 18.018.1 Basset-Seguin N, Ibbotson SH, Emtestam L, Tarstedt M, Morton C, Maroti M, et al. Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial. Eur J Dermatol 2008 Sep;18(5):547-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18693158.
  19. 19.019.119.2 Rhodes LE, de Rie MA, Leifsdottir R, Yu RC, Bachmann I, Goulden V, et al. Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma. Arch Dermatol 2007 Sep;143(9):1131-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17875873.
  20. 20.020.120.2 Horn M, Wolf P, Wulf HC, Warloe T, Fritsch C, Rhodes LE, et al. Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment. Br J Dermatol 2003 Dec;149(6):1242-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14674903.
  21. 21.021.121.221.321.4 Foley P, Freeman M, Menter A, Siller G, El-Azhary RA, Gebauer K, et al. Photodynamic therapy with methyl aminolevulinate for primary nodular basal cell carcinoma: results of two randomized studies. Int J Dermatol 2009 Nov;48(11):1236-45 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20064185.
  22. Collier NJ, Haylett AK, Wong TH, Morton CA, Ibbotson SH, McKenna KE, et al. Conventional and combination topical photodynamic therapy for basal cell carcinoma: systematic review and meta-analysis. Br J Dermatol 2018 Dec;179(6):1277-1296 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29889302.
  23. Vinciullo C, Elliott T, Francis D, Gebauer K, Spelman L, Nguyen R, et al. Photodynamic therapy with topical methyl aminolaevulinate for 'difficult-to-treat' basal cell carcinoma. Br J Dermatol 2005 Apr;152(4):765-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15840111.
  24. Rhodes LE, de Rie M, Enström Y, Groves R, Morken T, Goulden V, et al. Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial. Arch Dermatol 2004 Jan;140(1):17-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14732655.
  25. Tope WD, Menter A, El-Azhary.R.A., Lowe NJ, Jarratt MT, Pariser DM et al. Comparison of topical methyl aminolevulinate photodynamic therapy versus placebo photodynamic therapy in nodular BCC. J Eur Acad Dermatol Venereol 2004 [cited 2018 Oct 12];18(Suppl 2):413-414 Abstract available at https://doi.org/10.1016/j.jaad.2003.10.419.
  26. Lindberg-Larsen R, Sølvsten H, Kragballe K. Evaluation of recurrence after photodynamic therapy with topical methylaminolaevulinate for 157 basal cell carcinomas in 90 patients. Acta Derm Venereol 2012 Mar;92(2):144-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21918794.

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