APPENDICES: a Systematic Review of Photodynamic Therapy in the Treatment of Pre-Cancerous Skin Conditions, Barrett's Oesophagu

Home , Methyl aminolevulinate

Health Technology Assessment 2010; Vol. 14: No.371 Health Technology Assessment 2010; Vol. 14: No. 37 Appendix 5 Pre-cancerous skin scoping

Appendix 6 Appendices Go to main text Skin cancer scoping Appendix 7 Barrett’s oesophagus scoping

Appendix 8 Oesophageal cancer scoping A systematic review of photodynamic Appendix 9 therapy in the treatment of pre- Lung cancer scoping cancerous skin conditions, Barrett’s Appendix 10 oesophagus and cancers of the biliary Biliary tract cancer scoping Appendix 11 tract, brain, head and neck, lung, Brain cancer scoping oesophagus and skin Appendix 12 Head and neck cancer scoping D Fayter, M Corbett, M Heirs, D Fox Appendix 13 and A Eastwood Actinic keratosis data extraction

Appendix 14 Bowen’s disease data extraction

Appendix 15 Basal cell carcinoma data extraction

Appendix 16 Barrett’s oesophagus data extraction

Appendix 17 Oesophageal cancer data extraction

Appendix 18 Lung cancer data extraction

Appendix 19 Biliary tract cancer data extraction

Appendix 20 Brain cancer data extraction

Appendix 21 July 2010 Head and neck cancer data extraction 10.3310/hta14370

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The website also provides information about the HTA programme and lists the membership of the various committees. DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37

Appendix 5 Pre-cancerous skin scoping

ne hundred and thirty-three publications, with 9. Baron E, Domingo DS, Hsia A, Colussi V, Oleinick N, Foster T, et al. Silicon phthalocyanine study designs that did not meet the inclusion O photodynamic therapy for treatment of cutaneous criteria for the review, reported on patients with neoplasms. J Invest Dermatol 2008;128:395. pre-cancerous skin conditions being treated with PDT. The references are listed below, in 10. Berking C, Herzinger T, Flaig MJ, Brenner M, alphabetical order; they have not been categorised Borelli C, Degitz K. The efficacy of photodynamic and may still contain a number of duplicate therapy in actinic cheilitis of the lower lip: a publications. prospective study of 15 patients. Dermatol Surg 2007;33:825–30. References 11. Berroeta L, Lewis-Jones MS, Evans AT, Ibbotson 1. Alexiades-Armenakas MR, Bernstein LJ, Chen SH. Woringer-Kolopp (localized pagetoid J, Jacobson L, Geronemus R. Laser-assisted reticulosis) treated with topical photodynamic photodynamic therapy of actinic keratoses: long- therapy (PDT). Clin Exp Dermatol 2005;30:446–7. term follow-up. Lasers Surg Med 2003;15(Suppl.):45. 12. Breuninger H, Bonnekoh B, Gollnick 2. Alexiades-Armenakas MR, Geronemus RG. H. Photodynamic therapy with Laser-mediated photodynamic therapy of actinic methylaminooxopentanoate (MetvixR) and a broad keratoses. Arch Dermatol 2003;139:1313–20. band light source (PhotoDyn 501): Experiences in complicated patients with actinic keratoses 3. Ammann R, Hunziker T. Photodynamic therapy for and basal cell carcinomas [Multiple letters]. mycosis fungoides after topical photosensitization JDDG (Journal of the German Society of Dermatology) with 5-aminolevulinic acid. J Am Acad Dermatol 2005;3:397. 1995;33:541. 13. Britton JER, Goulden V, Stables G, Stringer M, 4. Antoniou C, Katsambas A, Rigopoulos D, Palaskas Sheehan-Dare R. Investigation of the use of the E, Tsikrikas GN. Aminolevulinic acid: topical pulsed dye laser in the treatment of Bowen’s disease photodynamic therapy in skin cancers and solar using 5-aminolaevulinic acid phototherapy. Br J keratoses. Skin Cancer 1996;11:81–4. Dermatol 2005;153:780–4. 5. Attili S, Cochrane A, McNeill A, Camacho-Lopez 14. Brookes PT, Jhawar S, Hinton CP, Murdoch S, M, Moseley H, Ibbotson S, et al. An open pilot Usman T. Bowen’s disease of the nipple: a new study of ambulatory photodynamic therapy using a method of treatment. Breast (Edinburgh, Scotland) wearable, low-irradiance, organic LED light source 2005;14:65–7. in the treatment of nonmelanoma skin cancer. Br J Dermatol 2008;159:130–1. 15. Buchanan RB, Carruth JA, McKenzie AL, Williams SR. Photodynamic therapy in the treatment of 6. Bakos RM, Bakos L, Ferlin E, Cestari T, Orlandini T, malignant tumours of the skin and head and neck. Rezende R, et al. [Photodynamic therapy with delta- Eur J Surg Oncol 1989;15:400–6. aminolevulinic acid for superficial keratinocytic neoplasms.] An Bras Dermatol 2003;78:197–207. 16. Cairnduff F, Stringer MR, Hudson EJ, Ash DV, Brown SB. Superficial photodynamic therapy 7. Baptista J, Martinez C, Leite L, Cochito M. Our with topical 5-aminolaevulinic acid for superficial PDT experience in the treatment of non-melanoma primary and secondary skin cancer. Br J Cancer skin cancer over the last 7 years. J Eur Acad Dermatol 1994;69:605–8. Venereol 2006;20:693–7. 17. Calzavara-Pinton PG. Repetitive photodynamic 8. Baptista J, Paris F, Serrao V, Cochito M. Topical therapy with topical delta-aminolaevulinic acid as photodynamic therapy and imiquimod cream in the an appropriate approach to the routine treatment of treatment of actinic keratoses: a case report. Skin superficial non-melanoma skin tumours. J Photochem Cancer 2006;21:49–53. Photobiol B 1995;29:53–7.

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109. Tan B, Sinclair R, Foley P. Photodynamic therapy 119. Varma S, Anstey A, Wilson H, Kurwa HA. for subungual Bowen’s disease. Australas J Dermatol Photodynamic therapy for the treatment of Bowen’s 2004;45:172–4. disease, solar keratoses, and superficial basal cell carcinomas: 12 months experience with a novel 110. Toll A, Parera Ma E, Velez M, Pujol RM. light source. Br J Dermatol 1998;139:19. Photodynamic therapy with methyl aminolevulinate induces phototoxic reactions on areas of the nose 120. Varma S, Wilson H, Kurwa HA, Charman C. adjacent to basal cell carcinomas and actinic One year relapse rates for Bowen’s disease, basal keratoses. Dermatol Surg 2008;34:1145–7. cell carcinomas and solar keratoses treated by photodynamic therapy: analysis of 189 lesions. Br J 111. Toll A, Parera ME, Velez M, Pujol RM. Letter: Dermatol 1999;141:114–18. photodynamic therapy with methyl aminolevulinate induces phototoxic reactions on areas of the nose 121. Varma S, Wilson H, Kurwa HA, Gambles B, adjacent to basal cell carcinomas and actinic Charman C, Pearse AD, et al. Bowen’s disease, solar keratoses. Dermatol Surg 2008;34:1145–7; discussion keratoses and superficial basal cell carcinomas 7–8. treated by photodynamic therapy using a large- field incoherent light source. Br J Dermatol 112. Tosca AD, Balas CJ, Stefanidou MP, Katsantonis 2001;144:567–74. JC, Georgiou S, Tzardi MN, et al. Prediction of ALA-PDT efficacy through remote color inspection 122. Wang J, Gao M, Wen S, Wang M. Photodynamic and post therapy sequential histologic observations therapy for 50 patients with skin cancers or of skin malignancies. SPIE Proceedings Series precancerous lesions. Chin Med Sci J 1991;6:163–5. 1997;3191:221–30. 123. Wang JB, Gao ML, Wen SJ, Wang MJ. Study 113. Touma D, Yaar M, Whitehead S, Konnikov N, of photodynamic therapy in skin cancers and Gilchrest BA. A trial of short incubation, broad- precancerous lesions. SPIE Proceedings Series area photodynamic therapy for facial actinic 1993;1616:139–42. keratoses and diffuse photodamage. Arch Dermatol 2004;140:33–40. 124. Wang XL, Wang HW, Guo MX, Xu SZ. Treatment of skin cancer and pre-cancer using topical ALA-PDT: 114. Tschen E, Pariser D, Wong DS, Dunlap FE. a single hospital experience. Photodiag Photodyn Ther Photodynamic therapy using aminolevulinic acid for 2008;5:127–33. patients with nonhyperkeratotic actinic keratoses of the face and scalp: long-term histopathologic results 125. Weisser H, Meyer-Rogge D, Meyer-Rogge E. [First of a phase IV multicenter clinical trial. J Am Acad experiences in medical practice with the new Dermatol 2005;52:P164. topical photosensitizer MAOP for actinic keratosis and basal cell carcinoma.] Aktuelle Dermatologie 115. Tschen EH, Wong DS, Pariser DM, Dunlap FE, 2004;30:306–11. Houlihan A, Ferdon MB, et al. Photodynamic therapy using aminolaevulinic acid for patients 126. Wennberg AM, Lindholm LE, Alpsten M, Larko with nonhyperkeratotic actinic keratoses of the face O. Treatment of superficial basal cell carcinomas and scalp: phase IV multicentre clinical trial with using topically applied delta-aminolaevulinic 12-month follow-up. Br J Dermatol 2006;155:1262– acid and a filtered xenon lamp. Arch Dermatol Res 9. 1996;288:561–4.

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117. Usmani N, Telfer N, Stringer M, Stables G. 128. Wolf P, Fink-Puches R, Reimann-Weber A, Subungual Bowen’s disease treated by topical Kerl H. Development of malignant melanoma photodynamic therapy. J Am Acad Dermatol after repeated topical photodynamic therapy 2005;52:P164. with 5-aminolevulinic acid at the exposed site. Dermatology 1997;194:53–4. 118. Vaicova M, Ettler K. [Our clinical experience with the use of photodynamic therapy in patients 129. Wolf P, Rieger E, Kerl H. Topical photodynamic with the basal cell carcinoma and morbus Bowen therapy with endogenous porphyrins after (comparison of efficacy of two photosensitizers).] application of 5-aminolevulinic acid. An Cesk Dermatol 2004;79:200–4. alternative treatment modality for solar keratoses,

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Appendix 6 Skin cancer scoping

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Appendix 7 Barrett’s oesophagus scoping

even non-RCTs reported in 11 publications high-grade dysplasia in Barrett’s esophagus. Lasers Med Sci 2008;23:203–10. Swere identified, which reported on patients with 1–11 Barrett’s oesophagus being treated with PDT. 7. May A, Gossner L, Pech O, Fritz A, Gunter E, Mayer These were originally to be included in the main G, et al. Local endoscopic therapy for intraepithelial systematic review; however, as 24 publications high-grade neoplasia and early adenocarcinoma in reporting 11 RCTs were identified, these less Barrett’s oesophagus: acute-phase and intermediate robust non-randomised designs were subsequently results of a new treatment approach. Eur J excluded from the review. Gastroenterol Hepatol 2002;14:1085–91.

A further 96 publications with study designs that 8. Mellidez JC, Mackenzie G, Selvasekar C, Novelli did not meet the inclusion criteria for the review M, Thorpe S, Mosse C, et al. Reversal of Barrett’s were identified.12–107 The references are listed esophagus following photodynamic therapy using high dose 5 aminolevulinic acid activated by red or below in alphabetical order, they have not been green laser light. Gastroenterology 2005;128:A239. categorised and may still contain a number of duplicate publications. 9. Panjehpour M, Overholt BF, Phan MN, Haydek JM. Optimization of light dosimetry for photodynamic References therapy of Barrett’s esophagus: efficacy vs. Non-randomised controlled trials incidence of stricture after treatment. Gastrointest 1. Gross SA, Gill KR, Wolfsen HC. Comparative Endosc 2005;61:13–18. outcomes of photodynamic therapy and radiofrequency ablation for the treatment of 10. Panjehpour M, Phan MN, Overholt BF, Haydek JM. Barrett’s esophagus with high grade dysplasia. Optimization of light dosimetry for photodynamic Gastrointest Endosc 2008;67:A179. therapy of Barrett’s esophagus. SPIE Proceedings Series 2004;5315:100–6. 2. Jamieson N, Mosse A, Thorpe S, Novelli M, Bown S, Lovat L. High-grade dysplasia in Barrett’s 11. Phan MN, Panjehpour M, Overholt BF. esophagus: successful ablation by photodynamic Optimization of photodynamic therapy for therapy with ALA requires intensive therapy. Barrett’s esophagus: treatment efficacy and stricture Gastroenterology 2003;124:A298. incidence as a function of light dose. Gastroenterology 2004;126:A178. 3. Jamieson NF, Thorpe S, Mosse A, Bown SG, Lovat LB. High grade dysplasia in Barrett’s oesophagus: Other scoping publications successful ablation by photodynamic therapy with 12. Photodynamic therapy with porfimer sodium ALA requires intensive therapy. Gut 2003;52:73. for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, 4. Mackenzie G, Clark BR, Selvasekar C, Jamieson N, randomized phase III trial. [Erratum published in Novelli M, Thorpe S, et al. Photodynamic therapy Gastrointest Endosc 2005;62:488–498.] Gastrointest with 5 aminolevulinic acid for high grade dysplasia Endosc 2006;63:359. in Barrett’s esophagus: longterm follow-up of 51 patients. Gastroenterology 2005;128:A238. 13. Ackroyd R, Brown NJ, Davis MF, Stephenson TJ, Stoddard CJ, Reed MW. Aminolevulinic acid- 5. Mackenzie GD, Clark B, Selvasekar CR, Jamieson induced photodynamic therapy: safe and effective NF, Novelli MR, Thorpe SM, et al. Photodynamic ablation of dysplasia in Barrett’s esophagus. Dis therapy with 5 aminolevulinic acid for high grade Esophagus 2000;13:18–22. dysplasia in Barrett’s oesophagus: long term follow- up of 51 patients. Gut 2005;54:53. 14. Ackroyd R, Brown NJ, Davis MF, Stephenson TJ, Stoddard CJ, Reed MWR. Aminolaevulinic 6. Mackenzie GD, Jamieson NF, Novelli MR, Mosse acid-induced photodynamic therapy in the CA, Clark BR, Thorpe SM, et al. How light treatment of dysplastic Barrett’s oesophagus and dosimetry influences the efficacy of photodynamic adenocarcinoma. Lasers Med Sci 1999;14:278–85. therapy with 5-aminolaevulinic acid for ablation of 151

15. Ackroyd R, Kelty CJ, Brown NJ, Stephenson TJ, 26. Etienne J, Dorme N, Bourg-Heckly G, Raimbert Stoddard CJ, Reed MWR. Eradication of dysplastic P, Flejou JF. Photodynamic therapy with green Barrett’s oesophagus using photodynamic therapy: light and m-tetrahydroxyphenyl chlorin for long-term follow-up. Endoscopy 2003;35:496–501. intramucosal adenocarcinoma and high-grade dysplasia in Barrett’s esophagus. Gastrointest Endosc 16. Attila T, Kortan P, Kandel GT, Marcon N. 2004;59:880–9. Photodynamic therapy (PDT) for Barrett’s esophagus with high grade dysplasia (BE-HGD). 27. Foroulis CN, Thorpe JAC. Photodynamic therapy Gastrointest Endosc 2005;61:A127. (PDT) in Barrett’s esophagus with dysplasia or early cancer. Eur J Cardiothorac Surg 2006;29:30–4. 17. Ban S, Mino M, Nishioka NS, Puricelli W, Zukerberg LR, Shimizu M, et al. Histopathologic aspects of 28. Globe J, Kelty CJ, Smythe A, Ackroyd R. The effect photodynamic therapy for dysplasia and early of photodynamic therapy (PDT) on oesophageal adenocarcinoma arising in Barrett’s esophagus. Am motility in Barrett’s oesophagus. Gut 2004;53:118. J Surg Pathol 2004;28:1466–73. 29. Globe J, Smythe A, Kelty CJ, Reed MWR, Brown 18. Barr H, Shepherd NA, Dix A, Roberts DJ, NJ, Ackroyd R. The effect of photodynamic therapy Tan WC, Krasner N. Eradication of high- (PDT) on oesophageal motility and acid clearance grade dysplasia in columnar-lined (Barrett’s) in patients with Barrett’s oesophagus. J Photochem oesophagus by photodynamic therapy with Photobiol B Biol 2006;85:17–22. endogenously generated protoporphyrin IX. Lancet 1996;348:584–5. 30. Go JT, Dumot JA, Lopez R, Vargo J, Zuccaro G, Falk G, et al. Photodynamic therapy in Barrett’s 19. Barr H, Tan WC, Shepherd NA, Krasner esophagus with high grade dysplasia and intra- N. Photodynamic therapy (PDT) using mucosal carcinoma. Am J Gastroenterol 2006;101:66. 5-aminolaevulinic acid (5ALA) for oesophageal adenocarcinoma associated with Barrett’s 31. Gossner L, Stolte M, Sroka R, Rick K, May A, Hahn metaplasia. Lasers Med Sci 1997;12:291–2. EG, et al. Photodynamic ablation of high-grade dysplasia and early cancer in Barrett’s esophagus 20. Behrens A, May A, Gossner L, Gunter E, Pech O, by means of 5-aminolevulinic acid. Gastroenterology Vieth M, et al. Curative treatment for high-grade 1998;114:448–55. intraepithelial neoplasia in Barrett’s esophagus. Endoscopy 2005;37:999–1005. 32. Heller SJ, Van Dam J, Barr H. Eradication of high-grade dysplasia using 5-ALA and acid 21. Buttar NS, Wang KK, Lutzke LS, Krishnadath KK, suppression: a (photo)dynamic duo. Gastroenterology Anderson MA. Combined endoscopic mucosal 1997;112:2156–8. resection and photodynamic therapy for esophageal neoplasia within Barrett’s esophagus. Gastrointest 33. Hemminger LL, Wolfsen HC. Photodynamic Endosc 2001;54:682–8. therapy for Barrett’s esophagus and high grade dysplasia: results of a patient satisfaction survey. 22. Chen WR, Huang Z, Korbelik M, Nordquist RE, Liu Gastroenterol Nurs 2002;25:139–41. H. Photoimmunotherapy for cancer treatment. J Environ Pathol Tox 2006;25:281–91. 34. Hinnen P, de Rooij FWM, Hop WCJ, Edixhoven A, van Dekken H, Wilson JHP, et al. Timing of 23. Etienne J, Canard JM. [Photodynamic therapy in 5-aminolaevulinic acid-induced photodynamic liberal practice.] Acta Endoscopica 2007;37:397–8. therapy for the treatment of patients with Barrett’s oesophagus. J Photochem Photobiol B Biol 2002;68: 24. Etienne J, Dorme N, Bourg-Heckly G, Raimbert 8–14. P, Fekete F. [Local curative treatment of superficial adenocarcinoma in Barrett’s esophagus. First 35. Hur C, Wittenberg E, Nishioka NS, Gazelle GS. results of photodynamic therapy with a new Quality of life in patients with various Barrett’s photosensitizer.] Bull Acad Natl Med 2000;184:1731– esophagus associated health states. Health Qual Life 44; discussion 44–47. Outcomes 2006;4:45.

25. Etienne J, Dorme N, Bourg-Heckly G, Raimbert 36. Ikeguchi M, Lightdale CJ, Choi YA, Bukowski K. A P, Fekete F, Mercadier Mc, et al. Local curative new light delivery system for photodynamic therapy treatment of superficial adenocarcinoma in Barrett’s with aminolevulinic acid (ALA) for treatment esophagus. First results of photodynamic therapy of high-grade dysplasia in Barrett’s esophagus. with a new photosensitizer. Bull Acad Natl Med Gastrointest Endosc 2005;61:A233. 2000;184:1731–47. 37. Jamieson N, Thorpe S, Mosse A, Novelli M, Lovat 152 L, Bown S. Photodynamic therapy using mTHPC DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37

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65. Overholt BF, Panjehpour M. Barrett’s esophagus: 77. Panjehpour M, Overholt BF, Haydek JM, Dougherty photodynamic therapy for ablation of dysplasia, TJ. Photodynamic therapy with photofrin followed reduction of specialized mucosa, and treatment of by thermal ablation for elimination of dysplasia and superficial esophageal cancer. Gastrointest Endosc early cancer in Barrett’s esophagus: follow-up in 100 1995;42:64–70. patients. SPIE Proceedings Series 1998;3247:14–24.

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67. Overholt BF, Panjehpour M. Photodynamic therapy 79. Panjehpour M, Phan MN, Overholt BF. Relationship in Barrett’s esophagus. J Clin Laser Med Surg between acute mucosal injury, treatment efficacy 1996;14:245–9. and esophageal stricture following photodynamic therapy of Barrett’s esophagus. Gastrointest Endosc 2004;59:A251. 154 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37

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81. Pech O, Gossner L, May AD, Stolte M, Ell C. Long 92. Sylantiev C, Schoenfeld N, Mamet R, Groozman term results of PDT for early neoplasia in Barrett’s GB, Drory VE. Acute neuropathy mimicking esophagus. Gastrointest Endosc 2004;59:A257. porphyria induced by aminolevulinic acid during photodynamic therapy. Muscle Nerve 2005;31:390–3. 82. Peters F, Kara M, Rosmolen W, Aalders M, Ten Kate F, Krishnadath K, et al. Poor results of 93. Triadafilopoulos G. Photodynamic therapy for the 5-aminolevulinic acid-photodynamic therapy for treatment of patients with Barrett’s high-grade residual high-grade dysplasia and early cancer dysplasia and mucosal adenocarcinoma. Nat Clin in barrett esophagus after endoscopic resection. Pract Gastroenterol Hepatol 2005;2:136–7. Endoscopy 2005;37:418–24. 94. van Hillegersberg R, Haringsma J, ten Kate FJW, 83. Peters F, Kara M, Rosmolen W, ten Kate F, Bultje B, Tytgat GNJ, van Lanschot JJB. Invasive carcinoma Krishnadath S, et al. Endoscopic resection combined after endoscopic ablative therapy for high-grade with photodynamic therapy for high grade dysplasia dysplasia in Barrett’s oesophagus. Dig Surg and early cancer in Barrett’s esophagus. Gastrointest 2003;20:440–4. Endosc 2004;59:A251. 95. Wang KK, Buttar NS, Lutzke LS, Anderson MA, 84. Peters FP, Kara MA, Rosmolen WD, Aalders Krisnadath K. Long-term results of photodynamic MCG, Ten Kate FJW, Bultje BC, et al. Endoscopic therapy for Barrett’s esophagus. Gastrointest Endosc treatment of high-grade dysplasia and early stage 2000;51:4915. cancer in Barrett’s esophagus. Gastrointest Endosc 2005;61:506–14. 96. Wang KK, Gutta K, Laukka MA. Phototherapy of Barrett’s esophagus. SPIE Proceedings Series 85. Prasad GA, Wang KK, Buttar NS, Wongkeesong 1994;2133:33–8. L-M, Krishnadath KK, Nichols FC, III, et al. Long- term survival following endoscopic and surgical 97. Wang KK, Song L, Buttar N, Papenfuss S, Lutzke treatment of high-grade dysplasia in Barrett’s L. Barretts esophagus after photodynamic therapy: esophagus. Gastroenterology 2007;132:1226–33. Risk of cancer development during long term follow-up. Gastroenterology 2004;126:A50. 86. Prasad GA, Wang KK, Buttar NS, Wongkeesong L-M, Lutzke LS, Borkenhagen LS. Predictors of 98. Weiss A, Wiesinger H, Owen D. Photodynamic stricture formation after photodynamic therapy therapy of high grade dysplasia in Barrett’s for high-grade dysplasia in Barrett’s esophagus. esophagus: results from treatment of 17 patients. Gastrointest Endosc 2007;65:60–6. Gastrointest Endosc 2005;61:A145.

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Appendix 8 Oesophageal cancer scoping

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Appendix 9 Lung cancer scoping

ne hundred and seventy-seven publications, 3. McCaughan JS. Photodynamic therapy versus Nd- Yag laser treatment of endobronchial or esophageal with study designs that did not meet the O malignancies. Photodyn Ther Biomed Lasers inclusion criteria for the review, reported on 1992;1011:23–36. patients with lung cancer being treated with PDT. Details are lacking for many of these publications, 4. McCaughan JS. PDT of endobronchial tumors on so the categorisations may not be reliable. the same day as injection of the photosensitizer DHE photodynamic therapy. Clin Laser Mon There are 10 observational comparative studies, 1993;11:57–8. with sample sizes ranging from 29 to 687, although the sample size is unclear for one-half of them.1–10 5. McCaughan JS, Barabash R, Hawley P. Stage-III For some of these studies, all of the patients receive endobronchial squamous-cell cancer: survival after PDT, for others it is series of patients undergoing Nd-Yag laser combined with photodynamic therapy vs Nd-Yag laser or photodynamic therapy alone. treatment for lung cancer, only a proportion of SPIE 1991;1426:279–86. which receive PDT. 6. McCaughan JS, Jr, Barabash RD, Hatch DR, Eleven publications are described as trials but McMahon DC. Gold vapor laser versus tunable without a comparator group (Phase I/II/pilot argon-dye laser for endobronchial photodynamic studies), with sample sizes ranging from 9 to 54.11–21 therapy. Lasers Surg Med 1996;19:347–50.

One hundred and nineteen publications report 7. McCaughan JS, Jr, Dougherty TJ. Photodynamic case series;22–140 19 have over 100 patients, eight therapy repeated without reinjection of Photofrin publications report on case series with between (R) (porfimer sodium). SPIE 1998;3247:31–4. 50 and 100 patients, and 71 report less than 50 8. McCaughan JS, Jr, Hawley PC, Walker J. patients. For 21 publications it is not clear what Management of endobronchial tumors: a the sample size is. Many of these publications are comparative study. Semin Surg Oncol 1989;5:38–47. by the same authors and appear to be updated series of patients or duplicate reports published in 9. Moghissi K. Lasers in broncho-pulmonary cancer. different journals. Therefore, these publications Radiol Oncol 1994;28:359–64. may double count patients to a certain degree. 10. van Boxem AJ, Westerga J, Venmans BJ, Postmus Thirty publications report less than 10 PE, Sutedja G. Photodynamic therapy, Nd-YAG patients,141–170 16 of which are single case laser and electrocautery for treating early-stage reports.142,143,146,147,149,151,152,155–157,161,163,164,166,167,169 intraluminal cancer: which to choose? Lung Cancer 2001;31:31–6. A further seven publications remain uncategorised Experimental non-comparative studies (e.g. the paper is unavailable, it is unclear 11. Calzavara F, Tomio L, Norberto L, Peracchia A, what is being reported, or possible duplicate Corti L, Zorat PL, et al. Photodynamic therapy in 171–177 publication). the treatment of malignant tumours of the upper aerodigestive tract. Lasers Med Sci 1989;4:279–84. References Observational comparative studies 12. Friedberg JS, Metz JM, Stevenson J, Zhu T, Mick R, 1. Furukawa K, Okunaka T, Yamamoto H, Tsuchida Smith D, et al. Increased survival and local control T, Usuda J, Kumasaka H, et al. Effectiveness of is observed for patients with stage 3B non-small photodynamic therapy and Nd-YAG laser treatment cell lung cancer (NSCLC), secondary to malignant for obstructed tracheobronchial malignancies. Diagn pleural effusions and gross pleural carcinomatosis, Ther Endosc 1999;5:161–6. in a phase II trial combining surgery and photodynamic therapy. Chest 2002;122:166S. 2. Kato H, Okunaka T, Konaka C. Photodynamic therapy for bronchogenic carcinoma. Nippon Geka 13. Friedberg JS, Mick R, Stevenson JP, Zhu T, Gakkai Zasshi 1997;98:36–40. Busch TM, Shin D, et al. Phase II trial of pleural 165

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Appendix 10 Biliary tract cancer scoping

hirty publications, with study designs that did therapy for advanced bile duct cancer: evidence for improved palliation and extended survival. not meet the inclusion criteria for the review T Hepatology 2000;31:291–8. reported on patients with biliary tract cancer being treated with PDT. Details are lacking for many of 4. Dumoulin FL, Gerhardt T, Fuchs S, Scheurlen these publications, so the categorisations may not C, Neubrand M, Layer G, et al. Phase II study be reliable. of photodynamic therapy and metal stent as palliative treatment for nonresectable There is one comparative study, which is published hilar cholangiocarcinoma. Gastrointest Endosc in Korean;1 the information is taken from the 2003;57:860–7. English abstract, which provides no methodological details. This study, of patients with advanced hilar 5. Harewood GC, Baron TH, Rumalla A, Wang cholangiocarcinoma, is a retrospective analysis KK, Gores GJ, Stadheim LM, et al. Pilot study to assess patient outcomes following endoscopic of 27 patients who were treated with PDT under application of photodynamic therapy for advanced percutaneous cholangioscopy plus additional cholangiocarcinoma. J Gastroenterol Hepatol percutaneous biliary drainage compared with 20 2005;20:415–20. patients who were treated with endoscopic biliary drainage alone. 6. Kaya M, de Groen PC, Angulo P, Nagorney DM, Gunderson LL, Gores GJ, et al. Treatment Twelve publications are described as trials but of cholangiocarcinoma complicating primary without a comparator group (Phase I/II/pilot sclerosing cholangitis: the Mayo Clinic experience. studies), with sample sizes ranging from 1 to 44.2–13 Am J Gastroenterol 2001;96:1164–9. One of these, a Phase II trial of 24 patients with Bismuth III/IV cholangiocarcioma treated with 7. Ortner MA, Liebetruth J, Mansmann U, Voderholzer W, Michetti P, Schachschal G, et al. PDT after sensitization with Ps, also reports a Photodynamic therapy of malignant bile duct retrospective comparison with a historical control tumors. Gastroenterology 2003;124:A565. group of 20 patients who fulfilled the inclusion 4 criteria for the prospective study. 8. Pereira SP, Aithal G, Devlin J, Meadows HM. Photostent 1: a phase II trial of porfimer sodium Seven publications report case series with at least photodynamic therapy in locally advanced biliary 10 patients but all of them have less than 50 tract carcinoma. Gut 2006;55:A116. patients.14–20 Ten publications report fewer than 10 patients,21–30 three of which are single case 9. Pereira SP, Ayaru L, Rogowska A, Mosse A, reports.21–23 Hatfield ARW, Bown SG. Photodynamic therapy of malignant biliary strictures using meso- tetrahydroxyphenylchlorin. Eur J Gastroenterol References Hepatol 2007;19:479–85. Observational comparative studies 1. Cheon YK, Cho YD, Baek SH, Cha SW, Moon JH, 10. Pereira SP, Ragunath K, Devlin J, Meadows HM. Kim YS, et al. [Comparison of survival of advanced Preliminary results of a phase II trial to examine hilar cholangiocarcinoma after biliary drainage the safety and efficacy of porfimer sodium alone versus photodynamic therapy with external photodynamic therapy (PDT) in locally advanced drainage][see comment.] Korean J Gastroenterol biliary tract carcinoma (BTC). J Clin Oncol 2004;44:280–7. 2005;23:A4180.

Experimental non-comparative studies 11. Wiedmann M, Berr F, Schiefke I, Witzigmann 2. Berr F, Tannapfel A, Lamesch P, Wiedmann M. H, Kohlhaw K, Mossner J, et al. Photodynamic Endoscopic palliation of bile duct cancer with therapy in patients with non-resectable hilar photodynamic therapy. Hepatology 1997;26:200. cholangiocarcinoma: 5-year follow-up of a prospective phase II study. Gastrointest Endosc 3. Berr F, Wiedmann M, Tannapfel A, Halm U, 2004;60:68–75. Kohlhaw KR, Schmidt F, et al. Photodynamic 175

12. Wiedmann M, Caca K, Berr F, Schiefke I, Tannapfel Case reports (single case or fewer than 10 A, Wittekind C, et al. Neoadjuvant photodynamic patients) therapy as a new approach to treating hilar 21. Berr F, Tannapfel A, Lamesch P, Pahernik S, cholangiocarcinoma: a phase II pilot study. Cancer Wiedmann M, Halm U, et al. Neoadjuvant 2003;97:2783–90. photodynamic therapy before curative resection of proximal bile duct carcinoma. J Hepatol 13. Wolkersdorfer G, Emmanuel K, Denzer U, 2000;32:352–7. Puespoek A, Neureiter D, Kiesslich T, et al. P-150 Temoporfin improves tumoricidal efficacy of photodynamic 22. Burdick JS, Magee D, Miller G, Wright KB. therapy (PDT) for bile duct cancer. International Liver Biliary photodynamic therapy alternative delivery Cancer Association Annual Conference, Chicago, technique. Endoscopy 2000;32:S63. 2008. p. 60. 23. McCaughan JS, Jr, Mertens BF, Cho C, Barabash Case series (10 or more patients) RD, Payton HW. Photodynamic therapy to treat 14. Abulafi AM, Allardice JT, Williams NS, van Someren tumors of the extrahepatic biliary ducts. A case N, Swain CP, Ainley C. Photodynamic therapy for report. Arch Surg 1991;126:111–13. malignant tumours of the ampulla of Vater. Gut 1995;36:853–6. 24. Nanashima A, Yamaguchi H, Shibasaki S, Ide N, Sawai T, Tsuji T, et al. Adjuvant photodynamic 15. Itoi T, Sofuni A, Itokawa F, Shinohara Y, Takeda K, therapy for bile duct carcinoma after surgery: a Nakamura K, et al. Salvage therapy in patients with preliminary study. J Gastroenterol 2004;39:1095–101. unresectable hilar cholangiocarcinoma. Digestive Endoscopy 2006;18:232–8. 25. Ortner MA, Liebetruth J, Schreiber S, Hanft M, Wruck U, Fusco V, et al. Photodynamic therapy of 16. Maunoury V, Mordon S, Boyer J, Quentin V, Barthet nonresectable cholangiocarcinoma. Gastroenterology M, Laugier R, et al. Results of a multicenter open 1998;114:536–42. study of photodynamic therapy (Photofrin) in 49 patients with cholangiocarcinoma. Photodynamic 26. Rumalla A, Baron TH, Wang KK, Gores GJ, Therapy and Photodiagnosis in Clinical Practice, Stadheim LM, de Groen PC. Endoscopic application Brixen/Bressanone, 7–11 October 2008. of photodynamic therapy for cholangiocarcinoma. Gastrointest Endosc 2001;53:500–4. 17. Ortner M. Photodynamic therapy for cholangiocarcinoma. J Hepatobiliary Pancreat Surg 27. Suzuki S, Inaba K, Yokoi Y, Ohata K, Ota S, Azuma 2001;8:137–9. M, et al. Photodynamic therapy for malignant biliary obstruction: a case series. Endoscopy 2004;36:83–7. 18. Prasad GA, Wang KK, Baron TH, Buttar NS, Wongkeesong L-M, Roberts LR, et al. 28. Zoepf T, Jakobs R, Arnold JC, Apel D, Rosenbaum Factors associated with increased survival after A, Riemann JF. Photodynamic therapy for palliation photodynamic therapy for cholangiocarcinoma. Clin of nonresectable bile duct cancer – preliminary Gastroenterol Hepatol 2007;5:743–8. results with a new diode laser system. Am J Gastroenterol 2001;96:2093–7. 19. Shim CS, Cheon YK, Cha SW, Bhandari S, Kim YS, Cho YD, et al. Percutaneous transhepatic 29. Zoepf T, Jakobs R, Rosenbaum A, Apel D, Arnold photodynamic therapy for advanced bile duct JC, Riemann JF. Photodynamic therapy with cancer and role of intraductal ultrasonography 5-aminolevulinic acid is not effective in bile duct (IDUS) in the follow-up and response assessment. cancer. Gastrointest Endosc 2001;54:763–6. Gastrointest Endosc 2003;57:A199. 30. Zoepf T, Jakobs R, Arnold JC, Apel D. 20. Shim CS, Cheon YK, Cha SW, Bhandari S, Photodynamic therapy (PDT) for palliation of non Moon JH, Cho YD, et al. Prospective study of resectable bile duct cancer: first results with a new the effectiveness of percutaneous transhepatic diode laser system. Gastroenterology 1999;116:G2357. photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonography in response assessment. Endoscopy 2005;37:425–33.

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Appendix 11 Brain cancer scoping

orty-three publications, with study designs Many of the publications appear to be from the Fthat did not meet the inclusion criteria for same clinical groups (14 are authored by Muller the review, reported on patients with brain cancer et al. and six by Kostron et al.) and there may well being treated with PDT. Details are lacking for be significant overlap in the results presented many of these publications, so the categorisations (updating as more patients have been treated). may not be reliable. Muller et al. began two RCTs that were not completed (see Chapter 11, Stopped trials) and There are two studies with some form of some of the publications authored by them appear comparison group, but both studies are poorly to report characteristics of the cohort of trial reported and lack methodological details.1–2 patients, but not comparative results.

One comparative study reports the results of a References Phase II trial of PDD/PDT in 26 patients with Observational comparative studies WHO grade IV recurrent glioblastoma who were 1. Chen ZQ, Wu S, Zhu SG. Adjuvant photodynamic sensitised with mTHPC (FOSCAN) prior to therapy in surgical management of cerebral tumors. fluorescent guided resection and intraoperative SPIE 1993;1616:94–7. PDT after 4 days.2 This group of patients was compared with a control group of matched 2. Kostron H, Fiegele T, Akatuna E. Combination of patients, but no details of how they were matched FOSCAN mediated fluorescence guided resection and photodynamic treatment as new therapeutic are provided. concept for malignant brain tumors. Med Laser Appl 2006;21:285–90. The other comparative study reported on 30 patients [27 glioma (nine of which were Experimental non-comparative studies recurrences), two malignant meningioma, two 3. Fedulov AS, Sakovich II, Sliakhtsin SV, Trukhachova metastatic brain cancer] treated with high-dose TV. PDT of high-grade gliomas with Fotolon. PDT (haematoporphyrin derivative and pumped Results of an open-label randomized clinical trial. dye laser) in addition to craniotomy with a radical Photodiagn Photodyn Ther 2008;5(Suppl. 1):S7. or partial excision of the tumour.1 The authors state that 30 comparable patients who were treated with 4. Kostron H, Fritsch E, Grunert V. Photodynamic surgery alone were selected at random as control therapy of malignant brain tumours: a phase I/II subjects, but no details are provided so it is not trial. Br J Neurosurg 1988;2:241–8. clear how these patients were selected. 5. Laws ER, Jr, Cortese DA, Kinsey JH, Eagan RT, Anderson RE. Photoradiation therapy in the Thirteen publications are described as being trials treatment of malignant brain tumors: a phase I but without a comparator group, the number of (feasibility) study. Neurosurgery 1981;9:672–8. patients ranging from 3 to 186.3–15 Some of the publications appear to be related, either potential 6. Marks PV, Belchetz PE, Saxena A, Igbaseimokumo duplicate publications or reporting different U, Thomson S, Nelson M, et al. Effect of outcomes for the same patients. photodynamic therapy on recurrent pituitary adenomas: clinical phase I/II trial: an early report. Twenty-two publications report case series with at Br J Neurosurg 2000;14:317–25. least 10 patients16–37 and six publications report 7. Muller P, Wilson B, Dougherty TJ. Photodynamic less than 10 patients,38–43 two of which are single 38–43 therapy of supratentorial gliomas. SPIE case reports. Of the 22 publications, four had 1997;2972:14–26. between 50 and 100 patients,26,27,29,30 and only three had more than 100 patients (one of which included 8. Muller P, Wilson B, Lilge L, Hitchcock M, Hertzel F, various treatments and so not all patients will have Chen Q, et al. Photodynamic therapy of malignant undergone PDT).32,33,35 brain tumors: results from a Phase II trial and

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demographics from a Phase III trial [Abstract.] Can 20. Kostron H, Grunert V. [Photodynamic therapy J Neurol Sci 1999;26:S31. of malignant brain tumors.] Wien Klin Wochenschr 1987;99:389–92. 9. Muller P, Wilson B, Lilge L, Varma S, Bogaards A, Fullagar, et al. Clinical studies of photodynamic 21. Kostron H, Obwegeser A, Jakober R, Zimmermann therapy for malignant brain tumors: facial nerve A, Rueck A, Dougherty TJ. Experimental and palsy after temporal fossa photoillumination. SPIE clinical results of mTHPC (Foscan R)-mediated 2003;4952:97–103. photodynamic therapy for malignant brain tumors. SPIE 1998;3247:40–5. 10. Muller P, Wilson B, Lilge L, Yang V, Hetzel, Chen Q, et al. Photofrin: Photodynamic therapy for 22. Kostron H, Plangger C, Fritsch E, Maier H. malignant brain tumors. SPIE 2001;4248:34–45. Photodynamic treatment of malignant brain tumors. Wien Klin Wochenschr 1990;102:531–5. 11. Muller P, Wilson B, Lilge L, Yang V, Hitchcock M, Hetzel F, et al. Clinical trials of photodynamic 23. Kostron H, Weiser G, Fritsch E, Grunert V. therapy of malignant brain tumors. SPIE Photodynamic therapy of malignant brain tumors: 2000;3909:10–19. clinical and neuropathological results. Photochem Photobiol 1987;46:937–43. 12. Muller P, Wilson B, Lilge L, Yang V, Varma A, Bogaars A, et al. Clinical studies of photodynamic 24. McCulloch GA, Forbes IJ, See KL, Cowled PA, Jacka therapy for malignant brain tumors: Karnofsky FJ, Ward AD. Phototherapy in malignant brain score and neurological score in patients with tumors. Prog Clin Biol Res 1984;170:709–17. recurrent gloms treated with Photofrin-PDT. SPIE 2002;4612:40–7. 25. Mehrkens J, Stummer W, Beck T, Tonn J, Kreth F. Interstitial photodynamic therapy of recurrent 13. Origitano TC, Reichman OH. Photodynamic malignant gliomas using 5-aminolevulinic acid (5- therapy for intracranial neoplasms: development ALA). Neuro Oncol 2005;7:110. of an image-based computer-assisted protocol for photodynamic therapy of intracranial neoplasms. 26. Muller P, Wilson B. Photodynamic therapy Neurosurgery 1993;32:587–95, discussion 95–96. of malignant brain-tumors – supplementary postoperative light delivery by implanted optical 14. Rosenthal MA, Kavar B, Uren S, Kaye AH. fibers: field fractionation. SPIE 1991;1426:254–65. Promising survival in patients with high-grade gliomas following therapy with a novel boronated 27. Muller P, Wilson B, Dougherty TJ. Photodynamic porphyrin. J Clin Neurosci 2003;10:425–7. therapy of supratentorial gliomas. SPIE 1998;3247:2–13. 15. Varma AK, Muller PJ. Cranial neuropathies after intracranial Photofrin-photodynamic therapy for 28. Muller PJ, Wilson BC. Photodynamic therapy of malignant supratentorial gliomas: a report on 3 malignant primary brain tumours: clinical effects, cases. Surg Neurol 2008;70:190–3. post-operative ICP, and light penetration of the brain. Photochem Photobiol 1987;46:929–35. Case series (10 or more patients) 16. Beck TJ, Kreth FW, Beyer W, Mehrkens JH, 29. Muller PJ, Wilson BC. Photodynamic therapy Obermeier A, Stepp H, et al. Interstitial of malignant brain tumours. Can J Neurol Sci photodynamic therapy of nonresectable malignant 1990;17:193–8. glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX. Lasers Surg Med 30. Muller PJ, Wilson BC. Photodynamic therapy for 2007;39:386–93. recurrent supratentorial gliomas. Semin Surg Oncol 1995;11:346–54. 17. Chen L-f, Ke Y-q, Yang Z-l, Wang S-q, Xu R-x. [Effect of photodynamic therapy combined with 31. Muller PJ, Wilson BC. Photodynamic therapy for interstitial chemotherapy for gliomas.] Di Yi Jun Yi malignant newly diagnosed supratentorial gliomas. Da Xue Xue Bao 2005;25:116–18. J Clin Laser Med Surg 1996;14:263–70.

18. Kaneko S. Clinical results of stereotactic 32. Muller PJ, Wilson BC. Photodynamic therapy of intratumoral photodynamic therapy for malignant brain tumors: a work in progress. Lasers Surg Med brain tumors. Clin Lasers Diagn 2000;1:222–30. 2006;38:384–9.

19. Kaye AH, Morstyn G, Brownbill D. Adjuvant high- 33. Obwegeser A, Ortler M, Seiwald M, Ulmer H, dose photoradiation therapy in the treatment of Kostron H. Therapy of glioblastoma multiforme: cerebral glioma: a phase 1–2 study. J Neurosurg a cumulative experience of 10 years. Acta Neurochir 178 1987;67:500–5. 1995;137:29–33. DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37

34. Schmidt MH, Meyer GA, Reichert KW, Cheng application and efficacy. d. Brain neoplasms.] J, Krouwer HG, Ozker K, et al. Evaluation of Nippon Rinsho 1987;45:817–25. photodynamic therapy near functional brain tissue in patients with recurrent brain tumors. J Neurooncol 40. Muller PJ, Wilson BC. Photodynamic therapy: 2004;67:201–7. cavitary photoillumination of malignant cerebral tumours using a laser coupled inflatable balloon. 35. Stylli SS, Kaye AH, MacGregor L, Howes M, Can J Neurol Sci 1985;12:371–3. Rajendra P. Photodynamic therapy of high grade gliom: long term survival. J Clin Neurosci 41. Perria C, Carai M, Falzoi A, Orunesu G, Rocca 2005;12:389–98. A, Massarelli G, et al. Photodynamic therapy of malignant brain tumors: clinical results of, 36. Zhu SG. [Application of adjuvant photodynamic difficulties with, questions about, and future therapy in the treatment of malignant brain prospects for the neurosurgical applications. tumors.] Chin J Clin Oncol 1993;20:894–6. Neurosurgery 1988;23:557–63.

37. Zhu SG, Wu S, Chen ZQ, Sun W. Photodynamic 42. Powers SK, Cush SS, Walstad DL, Kwock L. therapy of recurrent cerebral glioma. SPIE Stereotactic intratumoral photodynamic therapy 1993;1616:115–18. for recurrent malignant brain tumors. Neurosurgery 1991;29:688–95; discussion 95–96. Case reports (single case or fewer than 10 patients) 43. Stummer W, Beck T, Beyer W, Mehrkens JH, 38. Benzer A, Putensen C, Kostron H. Photodynamic Obermeier A, Etminan N, et al. Long-sustaining therapy. Lancet 1989;2:382–3. response in a patient with non-resectable, distant recurrence of glioblastoma multiforme treated by 39. Kaneko S. [Photoradiation therapy (PRT). 7. interstitial photodynamic therapy using 5-ALA: case Clinical study of photoradiation therapy: clinical report. J Neurooncol 2008;87:103–9.

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Appendix 12 Head and neck cancer scoping

ne hundred and twenty-nine publications, 3. Smucler R, Vlk P. Combination of laser induced interstitial thermotherapy and photodynamic with study designs that did not meet the O therapy in the treatment of neck cancer. Lasers Surg inclusion criteria for the review, reported on Med 2006;39:S18. patients with head and neck cancer being treated with PDT. Details are lacking for many of these Experimental non-comparative studies publications, so the categorisations may not be 4. Biel MA. Photodynamic therapy as an adjuvant reliable. intraoperative treatment of recurrent head and neck carcinomas. Arch Otolaryngol Head Neck Surg There are three studies that appear to be 1996;122:1261–5. comparative, although the precise design is not clear for any of them.1–3 5. Buchanan RB, Carruth JA, McKenzie AL, Williams SR. Photodynamic therapy in the treatment of Fifteen publications are described as trials but malignant tumours of the skin and head and neck. Eur J Surg Oncol 1989;15:400–6. without a comparator group (Phase I/II pilot studies), with sample sizes ranging from 5 to 6. Calzavara F, Tomio L, Norberto L, Peracchia A, 4–18 121. Corti L, Zorat PL, et al. Photodynamic therapy in the treatment of malignant tumours of the upper Eighty-seven publications report case series;19–105 aerodigestive tract. Lasers Med Sci 1989;4:279–84. eight have over 100 patients,26–28,33,61,87,94,105 but not all of these contain patients with only head and 7. Carruth JA, McKenzie AL. Preliminary report of neck cancer; some studies report multiple cancer a pilot study of photoradiation therapy for the site series. Eleven publications report on case treatment of superficial malignancies of the skin, series, with between 50 and 100 patients, and 56 head and neck. Eur J Surg Oncol 1985;11:47–50. report less than 50 patients. For 12 publications 8. Carruth JAS, Barrett JM, Barnes DWH, Buchanan it is not clear what the sample size is.19,39,40,48,56,57,6 0,64,68,82,85,99 RB, Sansom JM. A trial of photodynamic therapy Many of these publications are by the for the treatment of tumors of the skin and head same authors and appear to be updated series of and neck, and the results of an experimental- patients, or duplicate reports published in different study to determine the interrelationships between journals. Therefore, these publications may double the tissue effects of ionizing radiation and count patients to a certain degree. photodynamic therapy. SPIE 1993;1616:14–19.

Nineteen publications report fewer than 10 9. Feyh J. Photodynamic therapy of head and neck patients,106–124 seven of which are single case tumors. Adv Otorhinolaryngol 1995;49:53–7. reports.108,110,112,115,120,121,124 10. Feyh J. Photodynamic treatment for cancers of the head and neck. J Photochem Photobiol B 1996;36: A further five publications remain 175–7. uncategorised.125–129 11. Grossweiner LI, Hill JH, Lobraico RV. References Photodynamic therapy of head and neck squamous Observational comparative studies cell carcinoma: optical dosimetry and clinical trial. 1. Inoue H. [Voice evaluation after photodynamic Photochem Photobiol 1987;46:911–17. therapy for laryngeal cancer.] Otolaryngol Head Neck Surg 1997;69:407–10. 12. Hopper C, Kubler A, Lewis H, Tan IB, Putnam G. mTHPC-mediated photodynamic therapy for 2. Lofgren LA, Hallgren S, Nilsson E, Westerborn A, early oral squamous cell carcinoma. Int J Cancer Nilsson C, Reizenstein J. Photodynamic therapy for 2004;111:138–46. recurrent nasopharyngeal cancer. Arch Otolaryngol Head Neck Surg 1995;121:997–1002. 13. Lou PJ, Jager HR, Jones L, Theodossy T, Bown SG, Hopper C. Interstitial photodynamic therapy 181

as salvage treatment for recurrent head and neck 26. Biel MA. Photodynamic therapy and the treatment cancer. Br J Cancer 2004;91:441–6. of head and neck neoplasia. Laryngoscope 1998;108:1259–68. 14. Rauschning W, Tan IB, Dolivet G. Photodynamic therapy (PDT) with mTHPC in the palliation of 27. Biel MA, Dougherty TJ. Photodynamic therapy advanced head and neck cancer in patients who using photofrin and foscan and the treatment have failed prior therapies and are unsuitable for of malignancies of the head and neck. SPIE radiotherapy, surgery or systemic chemotherapy. 1998;3247:25–30. J Clin Oncol 2004;22:5596. 28. Bloznelyte L, Cepulis V, Ponomarev I, Dougherty 15. Savary JF, Monnier P, Fontolliet C, Mizeret J, TJ. Intra-arterial PDT and ordinary PDT in head Wagnieres G, Braichotte D, et al. Photodynamic and neck cancer. SPIE 1996;2675:76–9. therapy for early squamous cell carcinomas of the esophagus, bronchi, and mouth with m-tetra 29. Cai WM. [Result and indication of photodynamic (hydroxyphenyl) chlorin. Arch Otolaryngol Head Neck therapy in the treatment of malignant tumors: Surg 1997;123:162–8. analysis of 165 patients.] Zhonghua Zhong Liu Za Zhi 1990;12:69–71. 16. Schweitzer VG. Photodynamic therapy: 1994 treatment of benign and malignant upper 30. Copper MP, Tan IB, Oppelaar H, Ruevekamp MC, aerodigestive tract disease. SPIE 1995;2371:403–17. Stewart FA. Meta-tetra(hydroxyphenyl)chlorin photodynamic therapy in early-stage squamous cell 17. Schweitzer VG, Dougherty TJ. Hematoporphyrin- carcinoma of the head and neck. Arch Otolaryngol mediated photodynamic therapy for treatment of Head Neck Surg 2003;129:709–11. head and neck cancer: clinical update 1996. SPIE 1996;2675:47–66. 31. Copper MP, Triesscheijn M, Tan IB, Ruevekamp MC, Stewart FA. Photodynamic therapy in the 18. Suhr MA, Hopper C, MacRobert AJ, Speight treatment of multiple primary tumours in the head PM, Kubler AC, Kunz L. [Clinical pilot study of and neck, located to the oral cavity and oropharynx. interstitial photodynamic therapy for treatment Clin Otolaryngol 2007;32:185–9. of advanced head and neck tumors.] Mund Kiefer Gesichtschir 2001;5:277–82. 32. Cuenca RE, Sibata CH, Downie GH, Brodish B, Camnitz P, Allison RR. Photodynamic therapy for Case series (10 or more patients) head and neck neoplasia using Photofrinin. Ann 19. Bagnato VS, Kurachi C, Ferreira J, Marcassa Surg Oncol 2006;13:16. LG, Sibata CH, Allison RR. PDT experience in Brazil: a regional profile. Photodiagn Photodyn Ther 33. D’Cruz AK, Robinson MH, Biel MA. mTHPC- 2005;2:107–18. mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: 20. Biel MA. Photodynamic therapy and the treatment a multicenter study of 128 patients. Head Neck of neoplastic diseases of the larynx, oral cavity, 2004;26:232–40. pharynx and tracheobronchial tree. SPIE 1993;1881:10–19. 34. de Haas ER, Sterenborg HJ, Neumann HA, Robinson DJ. The influence of light fractionation 21. Biel MA. Photodynamic therapy and the treatment on the response of superficial skin cancer to of neoplastic diseases of the larynx. Laryngoscope aminolevulinic-acid photodynamic therapy. J Invest 1994;104:399–403. Dermatol 2006;126:S73.

22. Biel MA. Photodynamic therapy of head and neck 35. Decorbiere S, Ouayoun M, Sequert C, Freche C, cancers. Semin Surg Oncol 1995;11:355–9. Chabolle F. Use of photodynamic therapy in the treatment of vocal cord carcinoma retrospective 23. Biel MA. Photodynamic therapy and the treatment study 1986–1992: on 41 cases. Photodyn Ther Biomed of neoplastic diseases of the larynx. SPIE Lasers 1992;1011:656–61. 1995;2395:239–44. 36. Delbove H, de Corbiere S, Fugain C, Freche C, 24. Biel MA. Photodynamic therapy and the treatment Chabolle F. [Photochemotherapy in the treatment of malignancies of the head and neck. SPIE of carcinoma of the vocal cords of early stage (Tis, 1995;2392:55–62. T1).] Ann Otolaryngol Chir Cervicofac 1996;113: 155–61. 25. Biel MA. Photodynamic therapy and the treatment of head and neck cancers. J Clin Laser Med Surg 37. Dilkes M, Bapat U. Foscan photodynamic therapy 1996;14:239–44. for early head and neck cancer. Otolaryngol Head 182 Neck Surg 2004;131:74–5. DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37

38. Dilkes MG, Benjamin E, Ovaisi S, Banerjee AS. 50. Ha XW, Sun XM, Xie JG, Fan XJ, Zhang YH, Treatment of primary mucosal head and neck Mei QC, et al. Clinical use of hematoporphyrin squamous cell carcinoma using photodynamic derivative in malignant tumors. Chin Med J therapy: results after 25 treated cases. J Laryngol 1983;96:754–8. Otol 2003;117:713–17. 51. Herzog M. [Photodynamic laser therapy and 39. Dilkes MG, DeJode ML, Gardiner Q, Kenyon GS, fluorescence diagnosis in squamous epithelial McKelvie P. Treatment of head and neck cancer with cancer of the oral cavity.] Fortschr Kiefer Gesichtschir photodynamic therapy: results after one year. 1993;38:139–43. J Laryngol Otol 1995;109:1072–6. 52. Herzog M, Fellbaum C, Horch HH. [Initial clinical 40. Dilkes MG, DeJode ML, Rowntree-Taylor A, experiences with the photodynamic therapy McGilligan JA, Kenyon GS, McKelvie P. m-THPC (PDT) of oral cavity carcinomas.] Dtsch Zahn Mund photodynamic therapy for head and neck cancer. Kieferheilkd Zentralbl 1992;80:141–3. Lasers Med Sci 1996;11:23–9. 53. Herzog M, Fellbaum C, Wagnermanslau C, Horch 41. Fan KF, Hopper C, Speight PM, Buonaccorsi G, HH. Clinical, MRI and histological results after MacRobert AJ, Bown SG. Photodynamic therapy photodynamic therapy (PDT) of oral-cancer. SPIE using 5-aminolevulinic acid for premalignant 1992;1645:52–5. and malignant lesions of the oral cavity. Cancer 1996;78:1374–83. 54. Hopper C, Fan K, Grant WE, Speight PM, Bown SG. Photodynamic therapy using 5-aminolaevulinic 42. Fan KF, Hopper C, Speight PM, Buonaccorsi GA, acid in oral malignancy and premalignancy. SPIE Bown SG. Photodynamic therapy using mTHPC 1995;2371:254–5. for malignant disease in the oral cavity. Int J Cancer 1997;73:25–32. 55. Jiang X. The application of laser and PDT to treatment recurrent cancer in the paranasal sinuses. 43. Feyh J, Bujia J, Kastenbauer E. [Photodynamic SPIE 1993;1616:127–8. therapy with hematoporphyrin derivatives in cervico-facial basaliomas and epidermoid carcinoma 56. Keller GS, Doiron DR, Fisher GU. Photodynamic in stage I and II.] Acta Otorrinolaringol Esp therapy in otolaryngology: head and neck surgery. 1993;44:121–4. Arch Otolaryngol Head Neck Surg 1985;111:758–61.

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Appendix 13 Actinic keratosis data extraction

186 187

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 mg/g MAL -values or formal tests of p -values or formal Authors’ conclusions PDT using a 1-hr incubation with 160 treating potential for have may cream AK lesions and offers mild relatively but regular practical advantages, substitution is not recommended As the authors Brief study appraisal some were there acknowledge, in the design of this important flaws including the lack of blinding study, response and having outcome assessors, rather rate judgements made clinically Although the mean than histologically. incubation and illumination times were to the protocol, consistent according of it was clear that a large proportion 1 PDT session only patients received and recommended) (when 2 are of lesions had not one-third around that the protocol Given been debrided. been followed to have does not appear or has not utilised PDT optimally, closely, with should be considered these results No caution. appear to have statistical significance making it difficult to out, been carried between differences assess the real groups treatment Interpretation

cm and mg/g 160 mg/g 77% + mg/g 76% mg/g group (11%) mg/g group 80 hr + 160 160 hr + + hr mg/g group CR was mg/g group hr mg/g groups (44–45%). For For (44–45%). mg/g groups d. Other AEs included skin Other d. mg/g groups (19% and 17%) mg/g groups 160 + 160 mg/g, 98% mg/g, 99% mg/g, mg/g 74% 3 hr mg/g, 96% mg/g, : About one-third of About one-third Note : mg/g. + 160 160 98% 80m/g, 80 160 80 hr mth) was rated at between 8.4 mth) was rated at between Most AEs were mild intensity and the AEs were Most + + + + + + cm by both investigator and patients both investigator cm by hr hr hr hr hr hr compared with between 26% and 45% for 26% and 45% for with between compared the other groups PDT sessions: two Patients who received the 1-hr for was lower Lesion recurrence and 3 the 80 than for debrided lesions in the 3 score VAS Cosmetic outcome (assessed by at 12 9.3 indicating an excellent cosmetic outcome AEs The most commonly local. majority were AE was erythema with a median reported duration of 17 burning sensation on skin, pruritis, pain, patients Four oedema and suppuration. not experienced SAEs but these were related to be treatment considered AE %: Treatment-related 1 3 1 3 1 1 not debrided as per protocol. lesions were the 3 For debrided lesions (89%) than non- higher for debrided (78%) in 97 patients (evaluated Lesion recurrence with 299 lesions that had responded rates recurrence The lowest completely): in the 3 occurred non- was 10% vs 14% for recurrence debrided lesions to normal activity QoL and return Lesion response (based on Morbidity Lesion response patients two 110 patients with 380 lesions, lesions excluded due to wrong with four (not lesion response Overall diagnosis). clear if CR) 85% 3 Results . . 2 ) 2 J/cm mW/cm hr) and dose MAL–PDT comparing hr or 3 mg/g) mg/g). Most lesions were Most lesions were mg/g). mg/g) as above mg/g) as above mg/g) as above 160 160 80 80 + + + + mg/g or 80 mm of surrounding area. Lesions area. mm of surrounding nm, intensity 70 – 190 nm, min. Any lesions without CR at 2 or Any min. hr hr hr mth were given 2nd PDT treatment. 2nd PDT treatment. given mth were Trial treatments Trial incubation time (1 (160 Intervention MAL–PDT (1 hr to remove using dermal curette prepared of 1-mm-thick layer scales and crusts. to each lesion and applied MAL cream to 5 for dressing with occlusive covered specified incubation period then wiped illuminated Lesions were off with saline. 570– lamp light (wavelength with red 670 The mean illumination time was around The mean illumination time was around 9.5 3 alternative non-CR at 6 mth offered Any treatment Comparator MAL–PDT (3 2nd comparator MAL–PDT (1 comparator MAL–PDT 3rd (3 to provide total light dose of 75 to provide Treatment details Treatment

yr or older Not stated Treatment intention Treatment Curative of lesion and Type(s) AK histology Primary Main eligibility criteria Patients of 18 with Fitzpatrick skin type II or with primary I, untreated, previously non-pigmented and non- AK lesions (up infiltrating Extensive lesions). to four exclusion criteria were reported characteristics Patient age not 56, % Male: The majority of reported. or fewer patients had three located most were lesions; on the face/scalp and were thick thin or moderately Concomitant treatment Population details Population et hr; hr; FU mth RCT mg/g) 54 Eight mg/g) mg/g) mg/g) hr; 160 hr; 80 hr; 80 hr; Study details Full Data source published paper Countrystated, Not ‘Europe’ English Language Study design of participants No. 119 Total: 112 randomised, (384 lesions) treated 28 (1 Intervention: 160 30 Comparator: (3 25 2nd Comparator: (1 29 Comparator: 3rd (3 of recruiting No. centres period Follow-up and frequency at wk 1 and 2, then at wk 1 and 2, 6 and 12 3, at 2, d, day(s); hr, hour(s); mth, month(s); wk, week(s); yr, year(s). yr, week(s); wk, month(s); mth, hour(s); hr, day(s); d, al. (2008) al. 188 Authors Braathen 189

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 This study was Authors’ conclusions PDT with and is safe aminolevulinate methyl AK in transplant recipients. for effective the risk of also reduce It may and AKs to invasive, of transformation SCC fatal, potentially Brief study appraisal of high quality in methods and generally As the population recruited reporting. transplant immunosuppressed were not be may the results recipients generalisable to other populations Interpretation Not 0.0003) = For the MAL–PDT group discomfort the MAL–PDT group For Week 16: For the MAL–PDT For 16: Week Morbidity was CR of 13/17 lesional areas there group There (95% CI 9 to 16) and PR in 3/17. AK of in size or number was no reduction and in all area in 1/17 MAL–PDT treated rate CR lesion Overall areas. placebo-treated placebo MAL–PDT was 56/62 and for for 0/67 ( p to normal activity QoL and return assessed AEs scale) was mild in 11/17 and VAS (using the moderate in 6/17 (1st illumination) – and moderate in 9/17 and severe mild in 6/17, Mild to moderate in 2/17 (2nd illumination). the MAL–PDT group AEs for intensity For oedema and crusting. included erthyema, discomfort was mild areas placebo treated in all cases Results

2 nm) mW/cm MAL–PDT vs PDT ) by a non-coherent light source light source a non-coherent ) by 2 hr. After removal of dressing and of dressing After removal hr. cm. Superficial curettage followed followed Superficial curettage cm. J/cm 4 x (emission spectrum 600–730 Comparator PDT with placebo cream: MAL but with placebo cream As for (75 Treatment details Treatment treatments Trial (within-participant with placebo cream comparison) Two Intervention MAL–PDT: 1 wk apart, treatments consecutive size of maximum on areas performed 4 of 1-mm-thick MAL cream application by dressing with an occlusive then covered 3 for using saline solution, cleaning of area at 80 PDT was delivered

yr hr before hr before g of oral yr 1 Population details Population intention Treatment Curative of lesion Type(s) and histology Mild to AK moderate Main eligibility criteria organ Male and female (18 transplant recipients with mild to or over) AK (confirmed moderate 4-mm punch biopsy by region). thickest from Patients with porphyria allergyor known to compounds or excipients were of the cream excluded characteristics Patient 76 % Male: 44–76 Age range: 61 Mean age: Most lesions were located on the face or either Lesions were scalp. or had received untreated ineffective previous 1 mth ago over treatment Concomitant treatment paracetamol 1 illumination and a fan was area used on the affected 161 FU RCT wk after One 42 et Authors Dragieva (2004) al. 188 Study details publications Linked Full Data source published paper Country Switzerland English Language Study design of participants No. 17 (34 lesional Total: AK; with 129 areas lesional areas two per patient were randomised for treatment) 17 Intervention: AK) (62 lesional areas 17 Comparator: AK) (67 lesional areas of recruiting No. Centres period Follow-up and frequency 8 and 16 4, 1, AEs 2nd treatment. at these also recorded and times and before after illumination 189

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 ) seems preferable when ) seems preferable 2 mW/cm Interpretation performing PDT of AK using non- PDT of performing light sources coherent The details of Brief study appraisal reported poorly this small trial were of the the reliability therefore the however, conclusions is unclear; that a larger authors acknowledge RCT is required Authors’ conclusions Photobleaching rate and primary dependent outcomes are treatment fluence rate A low on fluence rate. (30 0.02); 0.02); (narrow) (narrow) < 2 p mW/cm (narrow filter) group (8/9 filter) group (narrow 2 2 Not assessed J/cm There was no significant There 0.07). No significant difference was No significant difference 0.07). mW/cm = Results There was a significant There Morbidity fluence rate between correlation outcome ( and treatment the highest number of patients the highest number was in the with complete remission 30 patients). There was a non-significant There patients). a smaller proportion towards trend filter the narrow AK for of remaining ( p 45 between found and 50mW (broad) groups implying implying groups and 50mW (broad) outcome was treatment preferable attributable to fluence rate not spectral emission to normal QoL and return activity AEs fluence rate and between correlation up value increased VAS The score. VAS light dose to a peak after cumulative of 20 . . 2 ) 2 J/cm ) and after 2 ) took place J/cm 2 J/cm ALA–PDT (narrow filter). Total filter). (narrow 2 mW/cm (all treatments) 2 (broad filter) vs ALA–PDT filter) vs (broad ALA–PDT filter) vs (broad ALA– filter) vs (narrow total dose 100 , other filter); (broad other filter); (narrow other filter); (narrow 2 2 2 2 2 2 2 J/cm nm, 0.5 nm, mW/cm mW/cm mW/cm mW/cm mW/cm mW/cm mW/cm mW/cm hr. The Photo Demarcation System The Photo Demarcation hr. ALA–PDT: Crusts ALA–PDT: Intervention then 20% removed and scales were using an was applied ALA cream after bandage and removed occlusive 3 was used to deliver 5, Prototype 1, 50 Treatment details Treatment 75 30 PDT 45 details as before treatment ALA–PDT with 2nd comparator 30 details as before treatment ALA–PDT with comparator 3rd 45 details as before treatment finishing treatment (100 finishing treatment Fluorescence imaging recordings (365 imaging recordings Fluorescence and 405 Trial treatments Trial 50 ALA–PDT with Comparator 75 dose 100 before treatment, during treatment during treatment treatment, before 20 and 40 10, (after 5,

2 mm, or mm, cm yr Not stated Population details Population Treatment intention Treatment Curative of lesion and Type(s) AK histology Main eligibility criteria either AK; typical Clinically minimum AK lesion, one diameter of 20 lesions within area three exceeding 25 Patient characteristics Patient 80 % Male: 71 Mean age: located on Lesions were neck and scalp, the face, upper chest Concomitant treatment

) ) 2 2 ) mW/cm mW/cm 2 RCT wk 7 ) 2 mW/cm 43 mW/cm et al. Authors Ericson et al. (2004) Comparator: 10 (broad filter, filter, 10 (broad Comparator: 75 2nd Comparator: Nine 2nd Comparator: 30 filter, (narrow Study details Full published Data source paper Country Sweden English Language Study design No. of participants No. 40 (37 analysed) Total: Nine (broad Intervention: 50 filter, 190 Nine Comparator: 3rd 45 filter, (narrow centres of recruiting No. Multicentre period and Follow-up Frequency 191

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Few Few Interpretation Authors’ The conclusions excellent short- and long-term cosmetic results, recurrence low rate and high of patient and satisfaction physician associated with ALA–PDT indicate definite advantages other existing over modalities treatment AK for Brief study appraisal methodological reported, details were and details of the study population unclear. were of The sources appeared information contradictory in reporting that FU both ceased at and also 12 mth, 4 yr. for continued were The 4-yr results just for presented patients and four coupled with this, the lack of a clinically comparison relevant further treatment, questions the of the reliability authors’ conclusions. made (Attempts were to contact authors furtherfor details.) For ALA–PDT cosmetic For 75% clearance rate, by no. of patients : no. by 75% clearance rate, Severe stinging and/or burning was reported by at least by stinging and/or burning was reported Severe Results Morbidity of patients : no. by (100%), CR rate At wk 8, ALA–PDT vs 4/29 (14%) placebo 60/87 (69%) ALA-018: ALA–PDT vs 4/32 (13%) placebo 59/93 (63%) ALA-019: > At wk 8, ALA–PDT vs 6/29 (21%) placebo 68/87 (78%) ALA-018: ALA–PDT vs 8/32 (25%) placebo 71/93(76%) ALA-019: for the CR rate, pooled, trials were the two for When results was: of lesions, number ALA–PDT vs 122/302 (40%) 666/756 (88%) Lesion grade I: placebo ALA–PDT vs 52/199 (26%) 495/632 (78%) Lesion grade II: placebo at 8 wk re-treated 34% of patients were ALA–PDT group At wk 12 CR rate was 129/180 (72%) in the rate of A response patients. vs 7/61(11%) in placebo treated ALA–PDT patients in 158/180 (88%) of least 75% was reported The clearance rate was patients. vs 12/61(20%) placebo-treated facial lesions than scalp higher for patients (PDT group), of 32 lesions in four At 4 yr after PDT, and 22% (7) ‘recurrent’ 9% (3) were cleared, 69% (22) remained reported Furtherwere results ‘uncertain’. were to normal activity QoL and return in investigators ‘excellent’ by to ‘good’ was rated as response to ‘good’ as patients rated cosmetic response 92% of lesions; treated 85% of patients previously AK lesions; ‘excellent’ in 94% ALA–PDT for indicated a preference with 5-FU or cryotherapy management future for AEs In 99% less than 3% stopped treatment. 50% of PDT patients; erythematous shortly some or all lesions were of PDT patients, In 35% of PDT vs 79% in the placebo group. after treatment oedematous vs 0% in the patients some or all lesions were 4 wk. by or improved AE resolved Both types of placebo group. postPDT itching (26% vs 7%) ALA patients also reported More or not deemed remotely, patients had an SAE – all were Seven treatment to, related

2 J/cm ALA–PDT wk and all s) were applied. Lesions applied. s) were wk. After 12-wk long-term wk. Treatment details Treatment treatments Trial vs PDT with placebo cream ALA–PDT: Intervention ALA and 10 20% Topical of visible blue light (from of visible blue light (from for the BLU-U illuminator, 1000 were that had not cleared at 8 re-treated at re-evaluated patients were 12 was based lesion recurrence on complete chart review (including lesion photographs during most and treatment patient visits at wk recent 36–48) Comparator Not described

yr Not stated Population details Population intention Treatment Curative of lesion and Type(s) AK histology Main eligibility criteria Patients with AKs 4–15 grade I or II on the face or scalp. Excluded patients had a history of cutaneous photosensitisation, hypersensitivity porphyria, to porphyrins, photodermatosis or inherited or acquired coagulation defects characteristics Patient 90 % Male: 34–89 Age range: of treated The number lesions per patient ranged 4 to 15 from the were areas Treated but not both face or scalp, in the same patient Concomitant treatment mth, up mth, 162,163 162 RCT 1, 4, 8, and 12 8, 4, 1, 44 mth Fowler and Zax Authors Fowler (2002) Study details publications Linked Full published Data source A summary of results paper. of 2 trials with identical Results protocols. treatment only most outcomes were for as combined data. available obtained Further data were drugs.com from Country Not stated English Language Study design of participants No. Reported as being 243, Total: trials – 116 in two across and 125 in trial ALA-018, trial ALA-019 (which totals 241) 87 ALA-018: Intervention: 93 ALA-019: 29 ALA-018: Comparator: 32 ALA-019: centres of recruiting No. Multicentre period and Follow-up frequency to 48 wk, then FU at intervals of wk, 3 to 6 approximately 190 191

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Authors’ conclusions PDT with MAL–PDT is an excellent particularly for option, treatment damage patients with widespread AK lesions in cosmetically or areas sensitive Brief study appraisal a well-conducted Generally although study; and reported to likely the conclusions appear it should be noted be reliable, was delivered that cryotherapy accepted regimens’ ‘locally using clinical variation allowing the nine centres between Interpretation 0.001 < A 0.001; 76% 0.001; 0.013). 0.013). < = wk or less (all events). 1 MAL–PDT patient wk or less (all events). No systemic AEs were reported. The most reported. AEs were No systemic vs 56% as assessed by the patient, p the patient, vs 56% as assessed by Hypopigmentation was present in 5% MAL– Hypopigmentation was present sites. sites vs 29% cryotherapy PDT treated or tissue scar formation Hyperpigmentation, in less than 6% of total present were defects MAL–PDT patient satisfaction was lesion sites. in 61%, treatment rated better than previous Placebo-PDT in 15%. equal in 24% and worse patient satisfaction was rated better than previous surgery or 5-FU) in 21%, (cryotherapy, treatment in 64% equal in 14% and worse AEs 73% (74%). local reactions AEs were common AE after patients experienced at least 1 local the 1st PDT session and 66% after 2nd 30% after the 1st 35% after cryotherapy; session; Most of the and 27% after the 2nd placebo PDT. mild (48%) or were AEs in the MAL–PDT group AEs Other reported moderate (40%) intensity. burning sensation, common with MAL–PDT were: erythema (23.9%), painful skin (46%), stinging, blisters (3.4%), skin peeling (5.1%), oedema (8.5%), Median duration itching (5.1%) and crusting (2.3%). was 1 due to the burning sensation discontinued Lesion response rate was significantly rate was significantly Morbidity Lesion response 267/295) in the MAL–PDT group, higher (91%, 18/61) and (30%, than the placebo-PDT group p 278/407), (68%, group the cryotherapy higher in the thin Response rates were both. for thick lesions with lesions than the moderately response group, in the cryotherapy MAL–PDT; lesions thicker higher for rates were to normal activity QoL and return of MAL–PDT higher proportion significantly cosmetic outcome as patients graded overall patients (83% excellent than with cryotherapy p investigator, vs 51% as assessed by Results nm), nm), min hr mm , total , 2 mW/cm MAL–PDT vs PDT s (0.11) d . 2 identical lamps . 2 s (0.13); 10- to 20-mm s (0.13); s (0.15) and more than 20- s (0.15) and more mg/g) was applied (1 mg/g) was applied J/cm mm had a mean (SD) freeze mm had a mean (SD) freeze (Curelight, Photocure ASA, Oslo) ASA, Photocure (Curelight, 5.5cm illuminated fields with maximum time 10 mean exposure diameter, of six treatment with a maximum with acetate sheets and sites (mapped Anatomical per patient. AKs marked) photography landmarks and polaroid was This PDT procedure also used. after 7 repeated Comparator PDT with placebo: MAL–PDT but with colour- As for base instead of MAL matched cream AKs 2nd comparator Cryotherapy: frozen outlined and lesions were were The with a 1- to 2-mm rim. uniformly i.e. was used, accepted regimen locally specified a single-timed the protocol cycle with no exact freeze freeze–thaw of an formation time (the from ice ball to commencement of thawing). Lesions with a mean diameter less than 10 time of 0.12 lesions 0.16 mm lesions 0.26 Treatment details Treatment Trial treatments Trial vs conventional with placebo cream cryotherapy Scales Intervention MAL–PDT: and lesion removed and crusts were MAL with a curette. surface roughened (160 cream thickness) under occlusion for 3 thickness) under occlusion for light (570–670 then PDT with red intensities of 50–250 dose 75

yr mm) Population details Population intention Treatment Curative of lesion and Type(s) histology Mild to moderate AK non-pigmented Main eligibility criteria Patients with mild to AK moderate non-pigmented of the face or scalp suitable (with the cryotherapy for largest diameter of each lesion at least 5 characteristics Patient 70 PDT; 56 active % Male: 61 cryotherapy placebo PDT; 64 Mean age: 33–89 Age range: Cancer stage: 35 PDT; 209 active Grade I: 232 cryotherapy placebo PDT; 39 PDT; 151 active Grade II: 45 cryotherapy. placebo PDT; Caucasian, All patients were most had Fitzpatrick skin type I or II Concomitant treatment Not stated 45 FU of 164,165 Nine mth (after a run- wk) s, second(s). s, Study details Linked publications Full Data source published paper Country Australia English Language Study design RCT of No. participants 204 Total: 88 Intervention: AKs) (active (360 PDT) 23 Comparator: AKs) (placebo (74 PDT) 2nd Comparator: AKs) 89 (421 (cryotherapy) of No. recruiting centres 3 in period of up to 2 Follow-up Follow-up period and frequency 192 Authors (2003) Freeman 193

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 If short-duration As there were few few were As there Interpretation Authors’ conclusions as to be as effective ALA–PDT is shown be a 5% 5-FU at wk 12 and 26 then it may subjects for alternative suitable treatment AKs moderate to severe with multiple Brief study appraisal the efficacy in the abstract, details available was not described of the treatments the complete, and the study is not yet conclusion is of the author’s reliability made to contact (Attempts were unclear. the study author.) Not assessed At 1 wk FU ALA–PDT At 1 wk FU Results Morbidity Not assessed to normal QoL and return activity AEs signs of few patients showed scaling and (erythema, irritation 5-FU patients exhibited crusting); erythema moderate to severe ALA–PDT vs 5-FU nm). Treatment repeated at wk 8 if repeated Treatment nm). Treatment details Treatment treatments Trial Incubation with ALA–PDT: Intervention illumination 45–60 min before ALA for with a Blue Light PDT Illuminator (400– 450 in was less than a 75% reduction there No further details reported AKs. Application of 5-FU Comparator 5-FU: 2–4 wk for to the face or scalp twice daily as tolerated

Not stated Population details Population intention Treatment Curative of lesion and Type(s) histology AK Main eligibility criteria Participants with 5–20 lesions of moderate to eligible AKs were severe characteristics Patient Not stated Concomitant treatment 35 RCT FU at wk 4, FU at wk 4, One Authors Gupta (2004) 8, 12 and 26 8, Follow-up period and Follow-up frequency No. of participants No. 50 Total: 25 Intervention: 25 Comparator: of recruiting No. centres 192 Study details Abstract Data source Country Canada English Language Study design 193

appeared to be generally well well to be generally appeared it was unclear however, conducted; used and the were centres many how was sometimes reporting of results unclear Authors’ conclusions procedure one-step handle to easy an of isolated mild to therapy for Compared AK lesions. moderate pre- PDT procedures, with current is not curettage) (e.g. treatment needed and handling is considerably facilitated. rates superior to placebo Brief study appraisal Interpretation

ALA

0.0001 < 0.0001. Corresponding Corresponding 0.0001. < One AE was described as relating to AE was described as relating One 0.95). 95% of ALA–PDT patients 95% of 0.95). 0.0001) 0.35; investigator assessment 0.54). assessment 0.54). investigator 0.35; = < = Morbidity CCCR (lesions) was 82% ALA–PDT vs 19% (34/179) (316/384) for p placebo, for clearance rates on a patient basis were p 62% (41/66) vs 6% (2/33), QoL and return to normal activity QoL and return PDT between was no difference There or placebo in the cosmetic assessment lesions’ (patient assessment ‘cleared of p ‘normal’ Pigmentation status classed as 91% vs were ALA–PDT groups in the was no statistical difference There 12%. with placebo-PDT those treated from ( p very satisfied or with the were cosmetic outcome vs 44% with overall Patient satisfaction with placebo-PDT. with PDT outcome was greater overall ( p AEs (transient discoloration of the skin therapy ALA) with skin discoloration in one patient Transient ALA treatment. to was related local reactions overall patients had more (mostly was applied when treatment figure placebo 13% the 13%; vs 42% itching, the 2 trials) to be pooled from appears Results h mg of ALA–PDT patch 3nm) with an LED ) containing 8 ± 2 cm , 630 , 2 h, illumination with red light illumination with red h, J/cm source. Patients were instructed to Patients were source. 48 light for lesions from protect after therapy As for Comparator Placebo-PDT: ALA–PDT but with placebo on the patches 5-ALA was applied to lesions without 5-ALA was applied One patch per lesion. preparation. After 4 (37 Treatment details Treatment treatments Trial vs placebo PDT patch 3–6 ALA–PDT: Intervention patches (4 Not Caucasian mth prior Curative yr cm. The following The following cm. cm and interlesional distance wk before and during the study wk before Population details Population intention Treatment of lesion and histology Type(s) AK Main eligibility criteria (at least 18 yr males and females old) with skin types I–IV were AK lesions had inclusion. eligible for to be mild moderate (Cockrell diameter maximum a with definition) of 1.8 of at least 1 of child- women excluded: were non-responders bearing potential, patients with PDT, to previous particular dermatological conditions, dementia or clinically porphyria, topical immunosuppression, relevant response affect that may treatment 4 with treatment (various criteria), cytostatics or radiation 3 and intolerance to to/during study, ALA of ingredients characteristics Patient 82 % Male: Placebo 71.4 ALA 70.4; Age: Mean 51–89 Age Range: III 1% II 83%; I 9%; Type: Skin Concomitant treatment stated FU 166 29 Trial Trial 60 CCCR, Complete clinical clearance rate. Study details Data source Full published paper Country Germany Language English Study design RCT of No. participants 103 (587 Total: lesions) 69 Intervention: 34 Comparator: of No. recruiting centres after 12 wk (unclear whether each this was for trial) Follow-up period and frequency AK03 Linked publications 194 Authors Hauschild et al. (2008), 195

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 The Authors’ conclusions ALA–PDT is an easy to handle one-step procedure of isolated mild therapy for AK lesions. to moderate PDT with current Compared pre-treatment procedures, is not needed and handling facilitated. is considerably A single PDT treatment in efficacy rates being results significantly statistically superior to placebo and cryosurgery Brief study appraisal to be generally study appears conducted but reporting well of some the methodology was unclear and results Interpretation 0.87) = p Patients’ 0.007). 0.007). = 0.001). 95% of ALA–PDT 95% of 0.001). < 0.0001). Pigmentation status 0.0001). < 0.001 for both) 0.001 for 0.001) but the difference between between 0.001) but the difference < < 0.001) and cryosurgery ( p < Three per cent in the ALA and cryosurgery per cent in the Three The complete clinical clearance rates Morbidity 77% ALA–PDT, 89% (664/750) for (lesions) were cryosurgery(530/692) for and 29% (75/259) for better than placebo PDT was significantly placebo. PDT ( p Clearance rates (patients) were ALA–PDT 67% Clearance rates (patients) were cryosurgery 52% (66/126) and placebo 12% (86/129), better than placebo and PDT was significantly (5/43). cryosurgery ( p assessment of cosmetic outcome and investigators’ ALA– for better lesions was significantly of cleared PDT than cryosurgery ( p QoL and return to normal activity QoL and return very satisfied or with the patients were cosmetic outcome vs 82% with cryosurgery. overall ALA patients that to be reported It appears satisfied than placebo more significantly were and cryosurgery ( p classed as ‘normal’ in the ALA–PDT groups was ALA–PDT groups ‘normal’ in the classed as Hypopigmentation was seen in 33% of lesions 88%. Hyperpigmentation was seen in with cryosurgery. Pigmentation status 9% PDT patients vs 4% placebo. ALA–PDT and between different was significantly cryosurgery ( p ALA–PDT and placebo was not significant ( AEs to AE related an arms and 2% placebo reported ALA patients experienced an adverse 99% of therapy. (placebo data at some stage of treatment reaction AK03) was pooled with trial Results s) hr after ALA– ) containing 2 nm) with 3 cm ± , 630 , 2 J/cm mg of 5-ALA were applied to applied mg of 5-ALA were light illumination with red hr, Omnilux (11 centres). Patients Omnilux (11 centres). instructed to protect were 48 light for lesions from therapy Comparator cryosurgery : was protocol A standardised procedure Open spraying used. in 1 cycle with liquid nitrogen was used (with size C nozzles) time (of 5–10 and freeze started after ice ball formation 2nd comparator Placebo ALA–PDT As for PDT patch: but with placebo on the patches 8 lesions without preparation, After one patch per lesion. 4 (37 Treatment details Treatment treatments Trial PDT patch vs cryosurgery vs Placebo PDT patch Intervention ALA–PDT patch: 4–8 patches (4 cm. cm. Not stated cm and Caucasian wk before wk before Curative yr mth prior to/during study and Population details Population intention Treatment of lesion and histology AK Type(s) Main eligibility criteria (at least 18 yr old) males and females eligible for with skin types I–IV were AK lesions had to be mild inclusion. definition) with moderate (Cockrell diameter of 1.8 a maximum interlesional distance of at least 1 of women excluded: were The following non-responders child-bearing potential, patients with PDT, to previous particular dermatological conditions, relevant dementia or clinically porphyria, topical treatment immunosuppression, 4 response affect that may and during the study (various criteria), with cytostatics or radiation treatment 3 of placebo or intolerance to ingredients to cryotherapy reactions known characteristics Patient 72 % Male: cryosurgery 71, PDT 70, Mean age: placebo 72 41–94 Age range: IV 1% III 15%, II 66%, I 18%, Skin type: Concomitant treatment FU 166 29 Trial Trial 60 Study details Data source Full published paper Country Germany Language English Study design RCT of No. participants 349 (1950 Total: lesions) 148 Intervention: 149 Comparator: (cryosurgery) 2nd Comparator: 49 (placebo) of No. recruiting centres (unclear whether each this was for trial) Follow-up period and frequency after 12 wk AK04 Linked publications 194 Authors Hauschild et al. (2008), 195

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Interpretation Authors’ conclusions A-PDT patches PD P 506 the suitable for are of up to eight treatment AK lesions of mild to moderate intensity on and the head and face, results 4-hr application in excellent outcomes. Further Phase III trials to confirm required are these outcomes Brief study appraisal This study was relatively reported poorly making it difficult to assess the reliability of the methodology The use of or results. in a centres multiple small trial raises the possibility of centre- and on treatment effects Patients were outcomes. 8 up for followed only No statistical test wk. reported; were results it is difficult therefore to be confident in the conclusions of efficacy

Five patients reported AE patients reported Five Results Not assessed AEs to the study to be related considered moderate epistaxis headache, treatment: of alanine transaminase. and mild increase and during application Local reactions pruritis and incubation included burning, erythema – all but one case was rated Local reactions as mild or moderate. to be during illumination appeared 26% dose dependent and ranged from to 66% in the 4-hr in the 0.5-hr group were reactions Most frequent group. One patient’s burning and pruritis. pain, due to was interrupted treatment Almost all patients had local pain. severe with erythema, after treatment, reactions burning and desquamation, scabbing, Patients with pruritis being common. to clearance experienced local reactions extent than patients without a greater clearance The majority of lesions Morbidity clearance 8 wk after PDT and showed the showed the 4-hr incubation group – estimated 86% clearance best response selected as ‘statistically rate and this was All but 1 of the 12 the best treatment’. (details not similar results found centres lesions that In some patients, reported). at wk 4 then worsened ‘cleared’ appeared was most apparent wk 8 – this effect by and was not present in the 0.5-hr group, in the 4-hr group to normal activity QoL and return hr , , 2 J/cm 2-hr 4-hr + + 1-hr incubation: 1-hr incubation: 0.5-hr incubation: 0.5-hr incubation: + + mg of ALA. Patch ALA. mg of nm). Further PDT nm). Patch containing ALA (PD Patch containing Trial treatments treatments Trial 2 or 4 1, 0.5, to lesions for A) applied P 506 light illumination with red by followed Intervention PDT patch lesions per patient and four three Between using a PDT patch (one treated were per lesion) containing 8 occlusive provides therefore is lightproof lesion After patch was removed, protection. light (dose 37 illuminated with red Treatment details Treatment wavelength around 630 around wavelength not reported parameters were Comparator PDT patch see above 2nd comparator PDT patch see above incubation: comparator PDT patch 3rd see above incubation: wk cm cm. cm. yr cm and yr, yr, Any Any Caucasian yr, 70 yr, Curative wk prior to and yr, 70 yr, yr across groups yr across yr, 72 yr, respectively, for the four treatment treatment the four for respectively, groups located on the scalp Most lesions were was severity in all groups, or forehead mild and split between evenly fairly Mean lesion diameter was moderate. 8–9 at around groups similar across prior and during study Concomitant treatment Concomitant treatment able to affect other topical treatment AK not permitted 4 and salicylic acid- No urea during study. permitted 2 containing preparations Population details Population intention Treatment of lesion and histology AK Type(s) (mild to moderate) Main eligibility criteria aged at least 18 males or females confirmed mild to with histologically to required Lesions were AK. moderate diameter of 1.8 maximum have interlesional distance of at least 1 Patients with dermatological conditions were to impact on results likely Further eligibility criteria excluded. reported were characteristics Patient 74 % Male: 39–91 Age range: 72 Mean age: 55 Hauschild 12 Authors (2008) et al. Study details Full Data source published paper Country Germany English Language Study design RCT of No. participants 146 149: Total: patients completed of which 140 study, (520 lesions) were in the per protocol population 34 Intervention: (128 lesions) 0.5-hr incubation 38 Comparator: (138 lesions) 1-hr incubation 2nd Comparator: 34 (124 lesions) 2-hr incubation Comparator: 3rd 34 (130 lesions) 4-hr incubation of recruiting No. centres 196 period Follow-up and frequency 4 and 8 wk after treatment 197

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 The authors did Little useful wk Authors’ conclusions conclusions not report any Brief study appraisal this from could be retrieved evidence very few abstract which provided and details, methodological or result up small sample followed a fairly involved 16 for Interpretation Not of light resulted of light resulted 2 J/cm 2 J/cm The authors reported that The authors reported 0.001). At 16 wk. CR was seen in 56/66 At 16 wk. 0.001). < in a significantly better response than the better in a significantly although placebo group, corresponding between was no significant difference there at 2 the groups assessed AEs was seen in 11% of hyperpigmentation which was ALA–PDT, with AKs treated the placebo group. from not different tolerated and no was well The treatment AE due to an patients withdrew QoL and return to normal activity QoL and return At 8 wk, 66% of AKs treated AKs treated 66% of At 8 wk, Morbidity ALA had a CR vs 17% with placebo with ( p ALA–PDT patients (no results (85%) of with AKs treated placebo). reported for ALA–PDT at 5 or 10 Results . . 2 J/cm wk if necessary. wk if necessary. ALA–PDT vs PDT with Further PDT parameters were not reported Further PDT parameters were As above Comparator Placebo PDT: was used in place of except placebo control ALA solution Patients were re-treated at 8 at re-treated were Patients Trial treatments treatments Trial placebo (within-participant comparison) AKs were Two ALA–PDT: Intervention ALA solution (Levulan) with 20% treated and after 14- to 18-hr exposed blue 10 and 5 2, of doses (non-laser) light at Treatment details Treatment

Not Curative Type(s) of lesion Type(s) and histology AK Main eligibility criteria Patients AKs on with four the face and scalp Patient characteristics Not stated Concomitant treatment stated Treatment Treatment intention Population details Population 8 and Not 41 wk 16 stated multicentre Follow-up period and frequency Study details Data source Abstract Country USA English Language Study design RCT of No. participants 36 Total: 36 Intervention: 36 Comparator: of recruiting No. centres 196 et Authors Jeffes (1998) al. 197

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Authors’ conclusions MAL–PDT showed for efficacy inferior of non-face/ treatment with AK compared scalp However, cryotherapy. showed both treatments and MAL– high efficacy, the PDT conveyed advantages of better cosmesis and higher patient preference Brief study appraisal The study was quite but it conducted, well was open in design and was there therefore investigator/ potential for The patient bias. possibility of institutional and/or differences (24 deviation protocol countries) in four centres the reliability affecting was illustrated of results the wide variation of by timings used freeze–thaw cryotherapy for Interpretation 0.001). 0.001). < 0.001). Overall Overall 0.001). < Investigator-assessed Investigator-assessed 0.001), procedure (49% procedure 0.001), < 0.002), 95% CI of the bilateral 0.002), 0.001). 28% had no preference 28% had no preference 0.001). = < p 0.001) < 0.001). In the MAL–PDT group, 79% of lesions In the MAL–PDT group, 0.001). < 0.05) and healing (64% vs 6%, p 0.05) and healing (64% vs 6%, = There were 63% patients with 99 AEs with cryotherapy AEs with cryotherapy 63% patients with 99 were There 0.001). 76% (455) of lesions were cured with MAL–PDT cured 76% (455) of lesions were 0.001). < patient satisfaction favoured MAL–PDT (49% vs 20%, p MAL–PDT (49% vs 20%, patient satisfaction favoured If re-treatment was required 59% would prefer MAL–PDT over over MAL–PDT prefer would 59% required was re-treatment If p (25%, cryotherapy AEs Most were AEs with MAL–PDT. vs 45% patients with 67 The most commonly to treatment. dermatological and related MAL–PDT was photosensitivity reaction AE for reported injury AEs) and cold exposure for (43% of patients with 63 of mild Most were AEs). (62% patients with 95 cryotherapy reported group patients in the cryotherapy Two intensity. injury cold exposure severe Results cosmetic outcome was significantly better for MAL–PDT than better cosmetic outcome was significantly ( p cryotherapy 3% fair and 0% 19% good, had an excellent cosmetic outcome, 8% fair and 36% good, with 56% excellent, poor (compared 50% of patients After 24 wk, 0.9% poor with cryotherapy). MAL–PDT in terms of cosmetic outcome compared preferred ( p cryotherapy with 22% for At wk 24 the mean reduction in lesion count from in lesion count from At wk 24 the mean reduction Morbidity cryotherapy MAL–PDT and 88% for baseline was 78% for population) ( (per-protocol –16.6% and was between (MAL–PDT/cryotherapy) difference confirmed analysis ITT (last observation forward) carried 3.9%. with MAL–PDT vs 87% cryotherapy, this (75% reduction p was similar for The difference vs 88% (490) with cryotherapy. mild- and moderate-thickness lesions to normal activity QoL and return for MAL–PDT to cryotherapy Patients preferred (ITT analysis). 12% and (between all questions in the patient questionnaire apart from marked were The differences 58% of difference). MAL–PDT vs 26% (39% favoured of treatment effectiveness MAL–PDT in Patients preferred not significant). cryotherapy, p terms of comfort (60% vs 10%, p vs 28%, wk mm min MAL–PDT nm, dose nm, s) 14 ± s , mean time 8 , 2 J/cm s). Lesions with a non-CR s). hr (under occlusion). After hr (under occlusion). Treatment details Treatment treatments Trial (within- vs cryotherapy participant comparison) Intervention MAL–PDT: of lesions, After scraping of 160-mg/g a 1-mm layer to was applied MAL cream each lesion (including 5 tissue) for of surrounding 3 a standard saline cleansing, LED lamp illuminated lesions band red with narrow 630 light (average 37 36 after 12 re-treated were Comparator Cryotherapy: Double freeze–thaw using liquid cryotherapy with applied spray nitrogen rim a 1- to 2-mm frozen outside the lesion outline. Timing of freeze–thaw was as per usual application (mean practice of each centre time 20 yr yr Population details Population intention Treatment Curative of lesion Type(s) and histology Non- AK hyperkeratotic Main eligibility criteria Males and non-pregnant aged 18 or over, women with a clinical diagnosis of of AK, non-hyperkeratotic mild or moderate thickness, on locations other than the eligible were face or scalp, Patients had to inclusion. for comparable at least four have of similar AKs, symmetrical and total number severity on both sides of the body. Further eligibility criteria reported were characteristics Patient 65 % Male: 38–89 Age range: 68.9 Mean age: 687; Grade I, Cancer stage: 656 grade II, Patients had (a mean of) Further six lesions per side. patient characteristics were reported Concomitant treatment Not stated et FU RCT 24 46 al. (2008) al. Authors Kaufmann Study details Full Data source published paper Australia, Countries UK Germany, Belgium, English Language Study design of participants No. 121 (1343 Total: lesions) 121 (691 Intervention: lesions) 121 (652 Comparator: lesions) of recruiting No. centres 198 period Follow-up and frequency at wk 12 and 24. telephone Additional made at wk calls were 1 and 13 when patients re-treated were 199

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 This Authors’ conclusions with One treatment PDT using topical to be 5-ALA appears and well as effective tolerated as 3 wk of topical 5-FU, twice-daily and widely a cheap alternative available Appraisal to be study appeared too small to detect significant treatment The methods effects. not were and results reported and clearly to reduce measures randomisation, bias (e.g. blinding and allocation concealment) were not reported at all of so the reliability the conclusions is questionable Interpretation

2 mm Not assessed 0.72). No patients were No patients were 0.72). = p before treatment and 297mm treatment before 2 mth after treatment was 291 mth after treatment mm and 6 2 mm All patients experienced mild to moderate pain at PDT after (a reduction of 70%, 95% CI 61% to 80%). There was no There 95% CI 61% to 80%). of 70%, after (a reduction reduction of lesional area in significant difference statistically PDT and 5-FU at 6 mth ( between AKs with either treatment of cleared completely to normal activity QoL and return AEs painful than more significantly PDT sites were In wk 1, sites. was absent in wk 2 and reversed but this difference 5-FU sites, treatments between was no significant difference There in wk 4. symptom diaries were Daily the 4-wk period. over overall significantly PDT sites were In wk 1, 11 patients. completed by was erythematousmore than 5-FU sites but this difference was no There in wk 3 and 4. absent in wk 2 and reversed the over overall treatments between significant difference or scarring ulceration, was no blistering, There 4-wk period. One method. after either treatment photosensitivity reaction patient experienced contact sensitivity to 5-FU (a reduction of 73%, 95% CI 61% to 84%). For 5-FU, mean 5-FU, For 95% CI 61% to 84%). of 73%, (a reduction was 1390 lesional area The mean lesional area before treatment for for treatment before The mean lesional area Morbidity PDT was 1322 Results hr. hr. nm, nm, ALA–PDT ) 2 , mean fluence rate , 2 J/cm mW/cm wk by thorough massage thorough wk by 80 5-FU cream Comparator 5-FU cream topically (5%) was applied to one hand for twice a day 3 Treatment details Treatment treatments Trial vs 5-FU (within-participant comparison) ALA–PDT: Intervention Thick surface scale was then 20% if present removed topically 5-ALA was applied in a light- and covered 4 for impermeable dressing with PDT was administered a halogen lamp (580–740 150 It yr Treatment intention Treatment Curative of lesion and Type(s) histology AK Main eligibility criteria that patients with a appeared AKs affecting long history of and hands were the forearms inclusion eligible for characteristics Patient 47 % Male: 53–79 Age range: Concomitant treatment Not stated Population details Population 1 wk, 1 wk, RCT mth Not stated 47 wk and 6 Follow-up period Follow-up and frequency 4 Study details Full Data source published paper Country UK English Language Study design of participants No. 17 Total: 17 Intervention: 17 Comparator: of recruiting No. centres 198 et al. Authors Kurwa (1999) 199

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Few Few Interpretation methodological details were methodological details were in the abstract and provided of this small study the results not be generalisable may Authors’ conclusions PDT with fractionated and unfractionated illumination in effective similarly were pain However, AKs. reducing sensation during PDT was less intense with significantly fractionated than standard unfractionated illumination Brief study appraisal 14). 14). = 0.02). There was There 0.02). = 14, p 14, Not assessed = PDT induced pain (VAS score) score) PDT induced pain (VAS Results The mean number of AK of The mean number Morbidity by 12 and 24 was reduced at wk 4, 60 and 48% with unfractionated 65, and 50% with 53, PDT and 56, fractionated PDT respectively n not significant, (difference alternative seen for Similar results fractionated PDT group to normal QoL and return activity AEs unfractionated was 6.7 (SE 0.5) for fractionated PDT and 6.0 (0.5) for PDT ( n no significant difference in pain no significant difference fractionated and alternative between fractionated patients [8.0 (0.7) vs 8.2 (0.3) respectively]

2 J/cm PDT with fractionated divided by a dark interval divided by dark intervals with two of , 2 2 J/cm J/cm nm) of a single dose 37 hr, red light illumination (peak red hr, min min Treatment details Treatment treatments Trial illumination vs PDT with unfractionated Within-participant comparison, illumination. but six patients had PDT with fractionated fractionated illumination vs alternative pain after 1st due to severe illumination, fractionated dose Intervention PDT with unfractionated of MAL application Following illumination: 3 for cream emission 635 of 15 2nd comparator PDT with alternative PDT with As for fractionated illumination: unfractionated illumination except with three doses of 12.3 5 was applied Comparator PDT with fractionated PDT with unfractionated As for illumination: in two illumination except PDT was given doses of 18.5 yr yr Not stated Population details Population intention Treatment Curative of lesion and Type(s) histology AK criteria eligibility Main Not stated characteristics Patient 100 % Male: 59–84 Age range: 75 Median age: Patients had multiple AKs Patients had multiple Concomitant treatment 36 RCT FU at 4, 12 and FU at 4, wk Study details Abstract Data source Austria Country English Language Study design of participants No. AKs 47, 22 (mean number Total: range 17–89) AK not of 22 (no. Intervention: reported) AK not of 22 (no. Comparator: reported) AK of six (no. 2nd Comparator: not reported) centres of recruiting No. Not stated period and Follow-up frequency 24 200 (2006) Authors Legat et al. 201

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Both ALA and Both The abstract mth, so the reliability of the so the reliability mth, Interpretation provided few methodological details few provided up followed a small sample, and involved 1 only for conclusions is unclear Authors’ conclusions reduction in significant MAL–PDT result is no significant There AKs. in scalp ALA However, in efficacy. difference painful than MAL–PDT in the is more AKs scalp of extensive treatment Brief study appraisal

min, min, 0.085; 12 0.085; 0.044) = 1.9 (ALA) = ± 15) experienced 0.029. There was There 0.029. = = min, p min, 15) = min, p min, n 0.151; 6 0.151; = 3.2 (MAL) vs 6.2 All patients ( n 0.588) ( ± 0.012; 16 0.012; = min, p min, = Results by AK counts reduced Morbidity 5.6 ( p Not assessed AEs intensity on which was of greater pain, side at all time points: ALA treated the 3 QoL and return to normal activity QoL and return p also longer duration of discomfort post ALA ( p with treatment hr. Further PDT hr. MAL–PDT vs ALA– MAL–PDT vs hr. Further PDT hr. Treatment details Treatment treatments Trial PDT MAL cream Intervention MAL–PDT: 3 for was applied not reported parameters were ALA 20% ALA–PDT: Comparator 5 for was applied cream not reported parameters were yr Not Curative Treatment Treatment intention of lesion Type(s) and histology AK Main eligibility criteria Not stated Patient characteristics 100 % Male: 59–87 Age range: AKs All patients had on the scalp Concomitant treatment stated Population details Population RCT mth 1 Not stated 37 et al. et al. Authors Moloney (2007) Follow-up period and Follow-up frequency No. of participants No. 16 Total: 16 Intervention: 16 Comparator: of recruiting No. centres 200 Study details Abstract Data source Country Not stated English Language Study design 201

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 When This study Interpretation was generally well conducted and well was generally it was an open- however, reported; which can lead to bias label trial, of a particular treatment. in favour The possibility of institutional and/or protocol differences in two (25 centres deviation the reliability countries) affecting the was illustrated by of results times used for variation of freezing cryotherapy Authors’ conclusions with both MAL–PDT and treated patients significantly cryotherapy, for MAL–PDT treatment prefer MAL–PDT is an attractive AK. with AK, option for treatment comparable efficacy and superior with cosmetic outcomes compared cryotherapy double freeze–thaw Brief study appraisal 108) 108). At 108). 0.001, ITT 0.001, = 0.001, and 0.001, = < < 0.07), but there but there 0.07), 0.2, n 0.2, = = 0.001. Most subjects 0.001. < Overall participant Overall 0.24) after 1st treatment. For For 0.24) after 1st treatment. = 0.001). Reduction in lesion count at wk 24 was 89% 0.001). 0.001. Investigator preference for cosmetic outcome for preference Investigator 0.001. < < p Skin discomfort VAS scores (mean) were 5.2 with MAL– (mean) were scores VAS Skin discomfort At wk 12 lesion reduction with MAL–PDT was 87% At wk 12 lesion reduction Morbidity vs 76% ( Results with MAL–PDT vs 86% with cryotherapy ( p with MAL–PDT vs 86% cryotherapy wk 12 CR was 83% with MAL–PDT vs 72% with cryotherapy. At wk 12 CR was 83% with MAL–PDT vs 72% cryotherapy. wk 24 it was 86% (650/758) with MAL–PDT vs 83% (613/743) 21% of lesions with CR at wk 24 had needed with cryotherapy. at wk 12 vs 10% with MAL–PDT, with cryotherapy re-treatment grade or location (ITT independent of initial severity were results population) to normal activity QoL and return and skin discomfort) efficacy, cosmetic outcome, (i.e. preference ( p cryotherapy MAL–PDT vs 21% for was 49% for analysis). Results reported for per-protocol population were 45% population were per-protocol for Results reported analysis). p vs 10%, p was 52% vs 16%, preference overall for was 43% for MAL–PDT vs 12% for cryotherapy, p cryotherapy, MAL–PDT vs 12% for was 43% for ‘very satisfied’ with MAL–PDT (compared ‘satisfied’ to were 7/11 for AK treatments) other and previous with cryotherapy than 90% were More questions of a satisfaction questionnaire. of treatment, satisfied with MAL–PDT in terms of effectiveness at 1- and 3-mth FU. skin colour and appearance scarring, (92%) treatment over time taken for was preferred Cryotherapy to be re- prefer 65% would MAL–PDT. to 78% for compared ( n with MAL–PDT vs 32% cryotherapy treated AEs ( p PDT vs 4.9 with cryotherapy re-treated lesions, mean VAS scores were 3.7 vs 4.4. Patients 3.7 vs 4.4. were scores VAS mean lesions, re-treated in terms of skin discomfort after 1st cryotherapy preferred p 22%, no preference (45% vs 33%, treatment was no difference for re-treated lesions. Skin-related AEs were AEs were Skin-related lesions. re-treated for was no difference cryotherapy. 62% MAL–PDT patients vs 72% for reported by with MAL–PDT due to a local was one discontinuation There mild to moderate and AEs were Most skin-related reaction. transient wk nm, nm, MAL– mm s. s. s) 7 ) using 2 s (± min 41 mg/g cream was mg/g cream J/cm hr (under occlusion). hr (under occlusion). a standard LED light a standard Mean illumination source. time was 8 Lesions with a non-CR at 12 re-treated were Comparator Double cryotherapy: freeze–thaw spray Liquid nitrogen a 1- to to achieve applied rim around 2-mm frozen outline of the marked Mean freezing the lesion. time was 16 dose 37 Treatment details Treatment treatments Trial PDT vs cryotherapy (within-participant comparison) Intervention MAL– of After scraping PDT: of a 1-mm layer lesions, MAL 160 (including 5 applied tissue) for of surrounding 3 cleansing, saline Following illuminated lesions were light with narrowband 630 (approximately yr mth, regular regular mth, yr Not stated yr in Scotland) yr (16 mm Population details Population intention Treatment Curative of lesion Type(s) and histology Non- AK hyperkeratotic Main eligibility criteria over Males and females 18 with clinical diagnosis non- of (at least three) AK on hyperkeratotic the face and/or scalp and (of similar severity on both sides) number inclusion. eligible for were Patients that received within topical treatment 3 the previous patients UV therapy, with thick or pigmented were lesions or porphyria excluded characteristics Patient 91 % Male: 54–93 Age range: 75 Mean age: of lesions per Mean no. six side: Median lesion diameter: 7 Further patient characteristics were reported Concomitant treatment FU 167,168 48 25 Study details Linked publications Full Data source published paper Countries UK Ireland, English Language Study design RCT of No. participants 119 (1501 Total: lesions) 119 Intervention: (758 lesions) 119 Comparator: (743 lesions) of No. recruiting centres at wk 12 and Additional 24. telephone FU was at wk performed 1 and 13 Follow-up Follow-up period and frequency Authors Morton (2006) et al. 202 ultraviolet. UV, 203

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT Authors’ conclusions using topical MAL was a safe for treatment and effective AK with excellent cosmetic It is a promising outcome. that could benefit treatment further study from Brief study appraisal to be This study appeared conducted well generally Interpretation Investigator Investigator 0.001) For the MAL–PDT group the MAL–PDT group 0.001) For = 38 (90%) MAL–PDT patients had an AE vs 22 38 (90%) MAL–PDT patients had an For the MAL–PDT group, patient response patient response the MAL–PDT group, Morbidity For treatment was 32/39 (82%) vs 8/38(21%) in placebo, –61% ( p difference assessed cosmetic outcome in the MAL–PDT group in 31/32 (97%) patients and ‘good’ ‘excellent’ or was The patients this was 29/32 (91%). when assessed by either investigator ‘poor’ by outcome was not rated MAL–PDT to 73% of 32 patients preferred or patient. surgery) cryotherapy, (5-FU, treatments previous AEs One MAL–PDT patient discontinued (58%) in placebo. burning sensation AEs were: Common local AE. due to erythema (22 vs 8); of the skin (27 MAL patients vs 4); blisters (8 pain on the skin (10 vs 0); crusting (16 vs 6); stinging skin (6 vs 1) and skin oedema (6 vs 1); vs 2); details in paper More skin ulceration (5 vs 0). lesion response rate was 209/236 (89%) vs 92/241 lesion response mild Response rate was similar for placebo. (38%) for (90% and 84%, and moderate lesions in the MAL group was higher in the mild placebo response respectively); lesions (44% and 25%) to normal activity QoL and return Results hr mm (range , mean , 2 2 MAL–PDT ). Treatment Treatment ). J/cm 2 mW/cm mg/g) was applied mg/g) was applied mW/cm nm, dose 75 nm, intensity 155 50–200 was repeated after 1 wk was repeated Comparator PDT with MAL– As for placebo cream: PDT but with placebo cream Treatment details Treatment treatments Trial vs PDT with placebo cream Intervention MAL–PDT: Scales and crusts were MAL using a curette removed (160 cream (1-mm thickness and 5 mean 3 lesion) for around was Cream under occlusion. washed off using a 0.9% saline then a non-coherent solution, 570– light was applied: red 670 % mm yr yr with 4–10 previously yr with 4–10 previously Treatment intention Treatment Curative of lesion and Type(s) histology Mild and moderate AK Main eligibility criteria over Males and females 18 mild to moderate untreated AK on the non-pigmented face and scalp (at least 3 eligible for diameter) were Further eligibility inclusion. reported criteria were characteristics Patient 88 Male: 31–84 Age range: MAL–PDT 64; Mean age: placebo PDT 67 The majority of lesions mild and located on were Most patients were the face. Fitzpatrick skin type I or II Concomitant treatment Not stated Population details Population et al. et al. RCT FU was at 3 Five 49 mth. AEs were assessed AEs were mth. immediately during, at wk 2 and 3 after PDT, mth after the 2nd PDT treatment Follow-up period and Follow-up frequency No. of participants No. 80 (502 lesions) Total: Intervention 42 (260 lesion) 38 (242 Comparator: lesions) of recruiting No. centres Study details Full Data source published paper Country USA English Language Study design 202 Authors Pariser (2003) 203

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Given that Given This study Authors’ conclusions excellent MAL–PDT has proved superior to cosmetic outcomes, this suggests a therapy, conventional LED MAL–PDT using a red for role in patients with multiple light source AK lesions (up to eight) Brief study appraisal well to be generally appeared centre- conducted and explored although further on the results, effects details of the PDT light treatment been useful have would Interpretation 53) = n 0.16) 0.0001). 0.0001). = < 47) patients were: 47) patients were: = Not assessed Any AE/any local AE was local AE/any Any 0.16), no difference between between no difference 0.16), 0.0001). 3 mth after treatment 31% treatment after mth 3 0.0001). = < Morbidity Lesion CR rate was 86% OR placebo, MAL–PDT vs 52% for for p 6.9 (95% CI 4.7 to 10.3, Patient CR rate was 59% (29/49) MAL–PDT vs 15% (7/47) for for OR 13.2 (95% CI 4.1 to 43.1, placebo, p (15/49) MAL–PDT patients had 42 lesions vs 26% (12/47) placebo- new lesions. PDT patients with 34 new MAL–PDT patients had at least Four In the placebo. lesions vs two new five lesions 67% of new MAL–PDT group on the face vs 50% placebo were ( p lesions ( p location of new QoL and return to normal QoL and return activity AEs 98% (52/53) in the MAL– reported by 45% (22/47) reported PDT group. 45% (21/47) AE in placebo group, any In the MAL AE. local reported any 49% mild (vs 38%), 32% were group moderate (vs 6%) and 17% were were reported Commonly (vs 0%). severe the MAL–PDT ( AEs for local (vs placebo, n (vs placebo, skin burning erythema (77 vs 15%), pain of skin sensation (72 vs 11%), skin pruritis (23 vs 11%), (60 vs 21%), scab (26 vs 0%), oedema (28 vs 2%), blister (15 skin discomfort (23 vs 2%), (11 vs 4%) vs 0%) and skin exfoliation Results MAL– mm skin. mm skin. cm from skin). skin). cm from , 5–8 , 2 hr) and avoidance of hr) and avoidance J/cm This procedure was repeated was repeated This procedure after 1 wk Comparator Placebo PDT: MAL–PDT but with As for placebo cream Treatment details Treatment treatments Trial PDT vs Placebo Intervention MAL–PDT: of lesions by Preparation of scales and crusts removal then dermal curette, by of 1-mm-thick application to lesion and MAL cream 5 surrounding for applied dressing Occlusive at least 3 hr (permitted range 2.5–4 bright to sunlight, exposure indoor light and extreme then illuminated Area cold. 8 min) duration, (average LED (total dose with red 37 yr old with Not stated mth after Previously Previously Curative yr Population details Population intention Treatment of lesion and histology AK Type(s) Main eligibility criteria males and non-pregnant/ untreated with adequate non-lactating females contraception during and 1 at least 18 that were treatment non-hyperkeratotic 4–10 non-pigmented, grade I or II lesions on the face and scalp eligible (at least 3-mm diameter) were Exclusion criteria were inclusion. for immunosuppression, but included: extensive allergy allergy to MAL or similar, porphyria, regular antigens, or protein products to nut of face and scalp or treatment UV therapy topical 30 d, in previous with local therapy 3 mth in previous therapy characteristics Patient 82 % Male: Placebo PDT MAL–PDT 66.1; Mean age: 66.7 43–89 Age range: III/IV 27% II 50%; I 23%; Skin type: grade II 27% Grade I 73%; Grade of lesions: thin (grade The majority of lesions were About 50% of I) and located on the face. 8 and 10 lesions in patients had between total Concomitant treatment 169 et al. et al. RCT Eight 56 mth after last d, day(s). d, Study details publications Linked Full Data source published paper Country USA English Language Study design of participants No. 100 (723 lesions) Total: patients were (four ‘training’ as treated population) 49 (363 Intervention: lesions) 47 (360 Comparator: lesions) of recruiting No. centres Follow-up period Follow-up and frequency FU 3 204 Authors Pariser (2008) treatment 205

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT This hr of trial had only a small number a small number trial had only of Procedures of patients. randomisation and blinding of outcome assessors were No patient details unclear. Although the provided. were fractionated receiving group illumination had better outcomes, contribution of the the relative longer incubation time and the unclear. fractionated delivery are any were It is also unclear if there AEs Authors’ conclusions as fractionated delivered illumination with 16 a 2-hr incubation separated by dark interval improves significantly outcome in tumour therapeutic eradication Brief study appraisal Interpretation Not Not assessed At 24 wk, At 24 wk, Morbidity tumour was residual in 15 of 20 (75%) found biopsied patients in the single illumination, shorter-incubation was Treatment group. At 24 wk, repeated. was persistence there of tumour in 2 16 (13%) biopsied patients in the fractionated, group longer-incubation to QoL and return normal activity assessed AEs Results with cm 2 . Spraying of Spraying . J/cm 2 was delivered was delivered 2 J/cm mW/cm nm) was applied. The nm) was applied. . There was a 2-hr break was a 2-hr break There . 2 hr mW/cm nm) was applied. 100 nm) was applied. wk after illumination in patients with ALA–PDT with 16-hr incubation and two ALA–PDT with 16-hr incubation and two was delivered in 2 doses of 50 was delivered mm, covering the treated area, and 1 area, the treated covering mm, 2 J/cm between illuminations. Spraying of water and cooling with Spraying illuminations. between After the out to minimise pain sensations. fan was carried the for recommended sunblock ointments were treatments Biopsies measures. to sun protection in addition days next few 24 performed were detected after 4 fluorescence and ALA cream Comparator PDT with 5-hr incubation the illumination was as for for Preparation single light fraction: was then a 5-hr incubation period There intervention group. light (635 red before a fluence intensity of 30 in 1 dose, with a fluence intensity of 30 in 1 dose, measures and sun protection water and cooling with fans, performed Biopsies were the intervention group. as for were after 24 wk after illumination in patients whom fluorescence ALA was detected 3-hr incubation with Treatment details Treatment treatments Trial ALA–PDT with 5-hr incubation and a single light fractions vs illumination light ALA–PDT with 16-hr incubation and two Intervention with ointments 1st removed Thick crusts were fractions: with a saline After cleaning the area dressings). (and wet to a thickness of was applied ALA cream the 20% solution, 1 approximately of the surrounding skin. The area was covered by occlusive occlusive by was covered The area skin. of the surrounding to was placed on top in order Aluminium foil dressing. was then a 16-hr There ambient light. skin from protect light (635 red incubation period before total of 100

Population details Population Not stated Treatment intention Treatment Curative of lesion and Type(s) histology AK Main eligibility criteria histologically Previous AK confirmed diagnosis of characteristics Patient RCT wk 24 One 57 Authors Puizina-Ivic et (2008) al. Study details Full Data source published paper Country Croatia English Language Study design of participants No. 36 Total: Intervention: Fractionated 16 illumination: Single Comparator: 20 illumination: of recruiting No. centres Follow-up period and Follow-up frequency 204 205

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 ALA– Although Interpretation this trial used an intraindividual randomisation design for on it failed to report treatment, aspects of methods (including randomisation) and did not use an ITT analysis not Outcome assessors were investigator- blinded and only assessed cosmetic outcomes The results reported. were be little may suggest there PDT and between difference but grade I lesions, imiquimod for grade II be better for PDT may can be considered These results but reliable, moderately uncertainties do exist about the choice of statistical techniques the inconsistent reporting used, and the sample of some results, size (as the authors assumed that lesions within patients were independent) Authors’ conclusions PDT and imiquimod 5% cream for comparable treatments are ALA–PDT AK. upper extremity as a 1st- should be considered both grade I and for line therapy AK of the extremities grade II Brief study appraisal mth d. d. 0.05). 0.05). < Cosmetic outcome 0.05) < mth after treatment mth after treatment 0.05). There was also no There 0.05). > 0.05). Grade II CR for PDT Grade II CR for 0.05). < mth: The CR was 65% (81/124) for The CR was 65% (81/124) for mth: mth: PDT CR rates were significantly better significantly PDT CR rates were mth: No unexpected safety issues were recorded. PDT recorded. issues were No unexpected safety Results Morbidity 1 PDT CR for grade I and II lesions. and for overall imiquimod ( p 70% (87/124) and 18% (21/115) for Grade I lesion CR was 75% for PDT (50/67) and 34% Grade I lesion CR was 75% for imiquimod ( p (21/61) for was 65% (37/57), no grade II lesions achieved CR with no grade II lesions achieved was 65% (37/57), 6 imiquimod (0/54). but the difference imiquimod, PDT and 56% (64/115) for significant ( p was not statistically PDT) 72% (48/67, for grade I lesions, significant difference for higher significantly CR were imiquimod). vs 72% (44/61, 33/57) (58%, areas grade II lesions in the PDT treatment p 20/54, than with imiquimod (37%, to normal activity QoL and return 6 the investigators was assessed by erythema and pigment atrophy, to scarring, according fair or good, graded as excellent, Outcomes were change. were the groups between No significant differences poor. 85% in PDT and 75% excellent outcomes were observed; at 6 A patient-completed questionnaire imiquimod. for was The PDT procedure preferences. assessed treatment PDT in terms of 55% favoured 69% of patients, by preferred treatments for future PDT would prefer efficacy and 70% AEs burning (100%), stinging (83%), during treatment: reactions oedema (67%), moderate erythema (100%), pain (100%), no further tolerated, well Reactions were blistering (27%). within 7–15 and all resolved was required treatment application most commonly were Imiquimod reactions Local pain (4%). burning (11%), itching (21%), site related: mild to mostly were area in the treatment skin reactions intense during and more tolerated, moderate and well crusting (11%), erythema (93%), course 1 than 2: oedema (7%) (7%), erosions/ulcerations scaling (11%), . . , , 2 2 wk J/cm hr. hr. mW/cm mg of ALA–PDT hr. Illumination hr. d apart. Pain d apart. d/wk prior to sleep, cream cream d/wk prior to sleep, a Following wk (course 1). Trial treatments treatments Trial vs Imiquimod 5% intraindividual right/left comparison lesions ALA–PDT: Intervention crusts and removing by prepared lesions were where curettage, all these were not prepared applied cream 5-ALA 20% I. grade to lesions and 5-mm surrounding 4 skin and left for of removal following immediately red using non-coherent dressing light dose 75 light source, Treatment details Treatment and fluence rate of 75 (course 2) left on skin for at least 8 left on skin for for continued This treatment 4 period 4-wk post-treatment patients any observation, for repeated with lesions remaining a further for 4 the process management during treatment management during treatment included use of a fan and/or cooling sprays Comparator Imiquimod: based on approved treatment the head. for dosage regime 500 Patients applied for daily imiquimod 5% cream 3 Patients given two PDT sessions two Patients given 1st session targeting on same day, forearm, the hand and lower upper two-thirds 2nd treating complete Two of the forearm. delivered were PDT treatments 15 to all areas yr yr None cm, topical treatments topical treatments cm, invasive and any mth, Treatment intention Treatment Curative of cancer Type(s) and histology Non- AK hyperkeratotic Main eligibility criteria Clinical diagnosis of non- grade hyperkeratotic I (mild) and grade II AK on dorsa (moderate) of hands and forearms. Each patient required at least three to have lesions of comparable on each side of severity body (total of six lesions Exclusion minimum). any criteria were other dermatological diseases or conditions in or within area treatment 3 AK within previous for 2 tumours in the area treatment Patient characteristics 83 % Male: 64 Mean age: 49–79 Age range: of lesions: Severity 54% (PDT), Grade I: grade 54% (Imiquimod); 46% 46% (PDT), II: (Imiquimod) Concomitant treatment Population details Population RCT Not stated 61 mth after mth after last Authors Sotiriou et (2009) al. Follow-up period Follow-up and frequency up at 1 Followed and 6 No. of participantsof No. 30 (256 Total lesions) Intervention 30 (133 lesions) Comparator 30 (123 lesions) of recruiting No. centres a if given treatment; then 2nd treatment cycle final FU was at 6 treatment 206 Study details Full Data source published paper Country Greece English Language Study design 207

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Broad Broad This was a small study with poorly reported small study with poorly treatment Additional methodology. to patients that had severe was given been a have which may reactions, of The reliability factor. confounding uncertain is therefore the results Authors’ conclusions ALA plus with PDT treatment area activation with blue light appears as 5-FU in the to be as effective ALA plus laser light AK. of treatment than the less effective is somewhat therapies above Brief study appraisal Interpretation All three All three Four PDT-blue light and 3 PDT-laser patients light and 3 PDT-laser PDT-blue Four wk. Crusting and erosions were only seen with 5-FU. seen with 5-FU. only were Crusting and erosions wk. 75% or more lesions were cleared in 9/12 cleared lesions were Morbidity 75% or more vs 9/11 5-FU. light patients vs 5/12 PDT-laser PDT-blue light in 6/12 PDT-blue cleared 100% of lesions were The cumulative vs 6/11 5-FU. patients vs 1/12 PDT-laser AK lesion rate) was 80% clearance rate (or individual and 79% (5-FU) 50% (PDT-laser) light), (PDT-blue to normal activity QoL and return in global response, improvement showed treatments and mottled hyperpigmentation; tactile roughness tended towards light groups the 5-FU and PDT-blue the 5-FU whereas roughness, for tactile benefit more PDT- pigmentation. favoured groups and PDT-laser in which the signs of group blue light was the only based on the global resolved photoageing completely None of the treatments patients). (two score response signs of photoageing worsened AEs after reported mild or moderate stinging directly Erythema was the but not at subsequent FU. therapy 5-FU patients had the greatest AE; most pronounced erythema residual at and showed increase average 4 due in the 5-FU group was one discontinuation There confluent erythematousreaction to a severe Results

2 d J/cm hr to s. Two Two s. Broad area area Broad nm, 75 nm, d apart were d apart were hr, pulsed dye laser was pulsed dye hr, with 10-ms pulse duration using a 10-mm spot size, of each laser 10% overlap passes across impact and two Patients area). treatment 30 treatments two received apart 5% 2nd comparator 5-FU: applied cream fluorouracil 4 wk for once or twice daily Trial treatments treatments Trial ALA–PDT with blue light vs ALA–PDT with area broad laser light vs 5-FU ALA–PDT Intervention topical Following (blue light): 1 ALA for of application illumination with area, a broad 1000 blue-light PDT for 30 treatments applied Comparator ALA–PDT broad Following (with laser): ALA application topical area 1 for (595 administered Treatment details Treatment Treatment intention Treatment Curative of lesion and Type(s) histology AK Main eligibility criteria that Caucasian It appeared of patients with a minimum AK non-hyperkeratotic four of the face or scalp were inclusion eligible for characteristics Patient 81 % Male: ALA with blue Mean age: ALA with laser 58.9; light, 5-FU 64.3 light 61.0; 6–7 per of lesions: Mean no. patient Concomitant treatment dramatic Patients with more (6/11 cutaneous reactivity 5-FU and 1/12 PDT-laser with treated patients) were dilute acetic acid soaks potency and topical low (2–3 times corticosteroid daily) Population details Population FU RCT wk Not stated 50 wk and 4 Study details Full Data source published paper Country USA English Language Study design of No. participants 36 Total: Intervention 12 light) blue with (ALA 12 Comparator: (ALA with laser light) 2nd Comparator:12 (5-FU) of recruiting No. centres period Follow-up and frequency at end of treatment, 2 et al. Authors Smith et al. (2003) 206 207

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 The use of VPL The use of Minimal reporting of Interpretation means little can be both methods and results abstract this conference deduced from Authors’ conclusions in the is an efficient and useful alternative where AK, of photodynamic treatment can be a limiting otherwise pain development of PDT the performance factor for Brief study appraisal 0.425) = No significant differences No significant differences Pain assessment (VAS) Pain assessment (VAS) 0.292 = Results Morbidity Infiltration and No significant score: keratoses LED 0.86 between difference VPL 1.05 (0.74), (0.71) and p to normal QoL and return activity in patient satisfaction between ( p treatments AEs after PDT showed immediately for pain levels lower significantly VPL side (4.3 vs 6.4) the hr. One hr. (double 2 J/cm MAL–PDT with VPL MAL–PDT with ) with a pulse train 2 nm filtered hand piece. hand piece. nm filtered min) J/cm for 12 for 2 J/cm Treatment details Treatment See above Comparator PDT-LED: Trial treatments treatments Trial vs MAL–PDT with LED light (within- participant comparison) MAL cream Intervention PDT-VPL: 3 for to target area was applied VPL at 80 side received of 15 impulses, each of 5-ms duration, each of 5-ms duration, of 15 impulses, using a 610–950 LED light The opposite side received (37 pulsed at 40 yr Not Curative Population details Population Treatment Treatment intention of lesion Type(s) AK and histology Main eligibility criteria Not stated Patient characteristics 68 % Male: 73 Mean age: Concomitant treatment stated wk and 170–173 RCT FU at 2 38 mth Study details publications Linked Abstract Data source Country Not stated English Language Study design of participants No. 25 (238 lesions) Total: Not stated Intervention: Not stated Comparator: centres of recruiting No. Not stated period and Follow-up frequency et al. Authors Szeimies et al. (2007) variable pulsed light. VPL, 208 3 209

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT for treating AK treating PDT for In relation to CR, to CR, In relation Authors’ conclusions rate to cryotherapy, has a similar response and high but with superior cosmetic results patient satisfaction Brief study appraisal to only the authors’ conclusions appeared with uncertainty to thin facial lesions, relate (which frequently other results surrounding Cosmetic outcome and p -values). lacked based on smaller were satisfaction results The study was not blinded patient numbers. possibility which coupled with the real and protocol of institutional differences countries) casts in five (13 centres deviation of the results further doubt on the reliability Interpretation

0.035), where where 0.035), = Local AEs were reported by 44 reported by AEs were Local Cosmetic outcome was significantly Cosmetic outcome was significantly ( p better in PDT group and 98% of patients 96% of investigators graded outcome as excellent or good for respectively, (vs 81% and 91%, In the PDT group, group). cryotherapy patients treated of the 43 previously such as cryotherapy (various treatments 10 as and 5-FU) 32 rated PDT as better, than the previous and one worse equal, treatment AEs (43%) of PDT patients vs 26 (26%) The commonest patients. cryotherapy burning sensation (PDT 32% vs were skin pain (10% vs 9%), cryotherapy Three 13%) and crusting (5% vs 6%). due to local patients stopped treatment – one PDT (burning) and two reactions (pain) cryotherapy The overall CR rate The overall Morbidity PDT vs 75% was 69% (252/367) for Higher cryotherapy. (250/332) for observed in grade rates were response lesions. I (thin) lesions than in thicker the best Grade I facial lesions showed of intervention arm regardless response to normal activity QoL and return Results min. min. mg/g) . The . 2 hr, after hr, wk in lesions and a light 2 MAL–PDT vs mW/cm nm) with a total J/cm mm of surrounding normal mm of surrounding s. The freezing procedure was procedure The freezing s. intensity of 70–200 mean illumination time was 11 at treated Up to 10 lesions were The procedure the same session. after 1 was repeated not on the face or scalp (8% of patients) Comparator Cryotherapy: with superficial preparation cryotherapy by followed curettage, to spray with liquid nitrogen rim a 1- to 2-mm frozen achieve lesion outline. outside the marked time was The mean total freezing 24 cycles during the in two performed session single treatment Trial treatments treatments Trial Cryotherapy Loose Intervention MAL–PDT: using a removed crusts were and the surface gently curette (160 MAL cream roughened. as a 1-mm-thick layer was applied and to 5 with was covered The area tissue. 3 for dressing an occlusive was washed off which the cream by followed with a saline solution, illumination with non-coherent light (570–670 red light dose of 75 Treatment details Treatment yr yr wk when yr (PDT), 72 yr (PDT), yr old, with up yr old, 18 (cryotherapy) 58% of patients had 1–3 33% had 4–7 lesions, lesions, and 9% had 8–10 lesions. of thin mostly Lesions were (40%) or moderate (52%) located and most were grade, on the face (63%) or scalp (28%) Concomitant treatment Not stated Treatment intention Treatment Curative of lesion and Type(s) histology AK Main eligibility criteria Patients > AK lesions suitable for to 10 and no treatment cryotherapy within the last 4 Diagnosis was based eligible. on clinical assessment (and histology needed). where regular Patients receiving and patients UV therapy with pigmented lesions or excluded were porphyria characteristics Patient 61 % Male: 42–89 Age range: 71 Mean age: Population details Population At RCT 174,175 mth 13 51 wk and 3 Follow-up period Follow-up and frequency 2 Study details Linked publications Full Data source published paper Austria, Countries Italy, Germany, the Switzerland, Netherlands English Language Study design of participants No. 202 (732 Total: lesions) 102 Intervention: (384 lesions) 100 Comparator: (348 lesions) of recruiting No. centres 208 Authors Szeimies et (2002) al. 209

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Interpretation Authors’ conclusions MAL–PDT using Topical an LED is effective AKs multiple for treatment Brief study appraisal a well-conducted Generally centre trial that considered on the results; effects analysis a subgroup however, of patients that received painkillers may additional been useful have 0.04. 0.04. = Not assessed mth after treatment, mth after treatment, 0.001). At 3 0.001). < 0.001). Patient CR rate with MAL 0.001). < mm) on the face but better for large lesions mm) on the face but better for mm) on the scalp 85% (62/73) MAL patients reported AEs vs 60% 85% (62/73) MAL patients reported 20 Lesion response rate was 83% (348/418) Morbidity Lesion response OR 13.8 placebo, with MAL vs 29% (119/414) for p (9.5 to 19.9, was 68% (39/57) vs 7% (4/59) for placebo, OR 39.5 placebo, was 68% (39/57) vs 7% (4/59) for p (10.5 to 149.2, Results development of new lesions was 18% (10/56) in of new development p placebo, MAL patients vs 34% (20/58) for vs 59%. on the scalp in MAL group 73% were small lesions higher for Response rates were (3–10 (> to normal activity QoL and return AEs associated with treatment (35/58) and most were The most respectively). site (312/368 and 56/89, pain AEs with MAL were reported local commonly erythema of the skin 55% (40/73) vs 22% (13/58), and skin burning sensation 52% (38/73) vs 5% (3/58), In the placebo group 36% (26/73) vs 12% (21/58). AEs were most MAL mild; AEs were all but six local Nineteen MAL patients had severe mild to moderate. pain of the related: treatment AEs considered local skin burning sensation five, erythema six, skin 13, one and skin swelling scab one, four, skin exfoliation AEs: also six non-local were There one. face swelling oedema eyelid perspiration, dizziness and increased MAL Two reports) and headache (one report). (three skin pain due to severe patients discontinued hr , mean , 2 hr) under mg/g) , range 56– , J/cm 2 h of occlusion. h of occlusion. MAL–PDT vs mW/cm ) with the light source ) with the light source cm from skin. Breaks Breaks skin. cm from 2 mW/cm wk min, mean dose 37 min, 83 kept at 5–8 kept allowed in illumination were was that treatment provided completed within 4 after was repeated This process 1 As Comparator Placebo PDT: MAL–PDT but with placebo for cream intensity 74 Treatment details Treatment treatments Trial Placebo PDT After Intervention MAL–PDT: 1-mm- debridement of lesions, (160 thick MAL cream to each lesion and was applied 3 skin for 5-mm surrounding (permitted range 2.5–4 cleaned Lesions were occlusion. then with a saline solution, illuminated with non-coherent duration light (average LED red 9 22 Males and Curative yr skin type: I yr skin type: yr with 4–10 previously yr with 4–10 previously d, topical therapy in topical therapy d, mth mm untreated, non-pigmented, non- non-pigmented, untreated, grade I or II lesions hyperkeratotic on the face and scalp (at least 3-mm inclusion. eligible for diameter) were extensive Exclusion criteria were immunosuppression, and included: allergy to MAL or similar, porphyria, products to nut hypersensitivity regular antigens, or other protein of face or scalp in UV treatment 30 previous 3 previous characteristics Patient 79 % Male: Placebo MAL–PDT 69.5; Mean age: PDT 67.0 41–90 Age range: IV 10% III/IV 27%; II 44%; 19%; grade II grade I (thin) 41%; lesions: (moderate) 59% located The majority of lesions were patients had a on the face or scalp, lesions each and median of seven diameter was the median maximum 9 Concomitant treatment 8 placebo) patients (14 MAL, or oral analgesic treatment received patches fentanyl Population details Population intention Treatment of lesion and histology Type(s) AK Main eligibility criteria non-lactating women non-pregnant, 18 aged over FU 169 58 10 mth after last Study details Linked publications Full Data source published paper Countries USA Germany, English Language Study design RCT of No. participants 131 Total: Intervention: 57 (plus 16 not randomised – in included only AE analysis) 58 Comparator: recruiting of No. centres 3 treatment Follow-up Follow-up period and frequency 210 Authors Szeimies (2009) et al. 211

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Authors’ conclusions Single MAL–PDT treatment as a two- is as effective schedule for treatment Repeated AK lesions. thin is recommended treatment or non- thicker for lesions responding Brief study appraisal Although this study appears been quite well to have it was unclear conducted, whether the outcome blinded assessors were allocation. to treatment the recruited 21 centres five 211 patients (around participants per centre the increasing on average) possibility that protocol and institutional deviation affect would differences not p -values were results. reported Interpretation Cosmetic 75% of lesions in each group. 66% 75% of lesions in each group. AEs were reported in 42 single-treatment reported in 42 single-treatment AEs were Analyses based on 400 lesions (198 single Analyses Morbidity The lesion 202 double session MAL–PDT). session; vs 87% similar (81% single treatment CR rates were a CR A further 22 lesions showed 2 treatments). the single the CR for (increasing after re-treatment Single and two-treatment to 92%). group treatment thin lesions (93% vs schedules had similar CRs for thick lesions (70% vs moderately but not for 89%), after re-treatment although again this improved 84%), (88%) to normal activity QoL and return each of four outcome was rated as excellent for parameters in > who had previously patients, of single treatment PDT to preferred with cryotherapy, been treated group vs 58% in the two-treatment cryotherapy AEs Most patients. patients and in 53 two-treatment of mild to moderate intensity and AEs were local Burning of skin occurred short duration. relatively patients vs 19% of the in 15% of single treatment in 9% and pain occurred whereas group, treatment One patient randomised respectively. 18% of patients, due to moderate sessions discontinued to two completely) erythema (which resolved Results at 2 mth mW/cm wk apart MAL–PDT nm, light dose nm, 3 ± mm of surrounding mm of surrounding wk apart) , irradiance 50 irradiance , 2 mg/g) was applied to each mg/g) was applied J/cm mm from skin). Re-treatment if Re-treatment skin). mm from hr. The dressing was removed was removed The dressing hr. LED light (peak with red min, Treatment details Treatment treatments Trial single session vs MAL–PDT 2 sessions (1 Intervention MAL–PDT single lesion crust was Any session: or using a curette removed scalpel (without anaesthetic) and a of MAL (Metvix, 1-mm-thick layer 160 lesion and 5 with an tissue and covered mean of for dressing occlusive 3 washed off with and the cream 0.9% saline solution immediately mean of for illumination, before 8 634 wavelength 37 MAL–PDT two Comparator MAL–PDT two but two See above, sessions: 1 sessions, treatment 50 was a non-CR after 3 there Local Patients Curative yr with up to 10 yr single-session group, yr single-session group, yr 2-session group The majority of patients mm. Treatment intention Treatment of lesion and histology Type(s) AK (grade I or II) Main eligibility criteria aged at least 18 AK lesions on the diagnosed clinically mild which were face and/or scalp, (grade I) or moderate II) and eligible were non-pigmented, characteristics Patient 39 % Male: 69 Mean age: 68 one-half of the patients had Around AK. for prior treatment received Mean lesion diameter was around 10 had 1 or 2 (76–83% in both groups) on and 90% of lesions were lesions, being on the with the rest the face, Further characteristics were scalp. reported Concomitant treatment anaesthetic if needed during treatment Population details Population Full At 21 et al. et al. 52 mth Authors Tarstedt (2005) 3 Follow-up Follow-up period and frequency published paper Countr y Sweden Language English Study design RCT of No. participants 211 (413 Total: lesions) 105 Intervention: (198 lesions) 106 Comparator: (215 lesions) of No. recruiting centres 210 Study details source Data 211

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Short Little hr, yet no group no group yet hr, hr) broad area ALA–PDT area hr) broad information on methods and very information this very for presented limited results The conclusions appear small study. based on the were if they inappropriate short as appears incubation results, study to be defined as 1–3 long incubation treatment received Authors’ conclusions incubation (1–3 AKs in eradicating as effective appears with as the long incubation application, tolerable phototoxicity Brief study appraisal Interpretation

mth, mth, Phototoxic reactions were well well were reactions Phototoxic Results not broken down down Morbidity Results not broken but it was reported group, treatment by ALA of was no effect that there on any cream incubation time or urea At 1 outcomes. of the measured Patient satisfaction with cosmetic results and all high, was reported as moderately skin patients commented on improved texture AEs tolerated 90% of AKs had cleared (analysis on 17 (analysis AKs had cleared 90% of patients) to normal activity QoL and return Results ALA–PDT, 1-hr ALA–PDT, hr incubation: See above hr incubation: Trial treatments treatments Trial incubation vs 2-hr 3-hr incubation Pre- Intervention 1-hr incubation: cream with 40% urea treatment (penetration enhancer) and xylocaine by followed HCL 3% (pain control) ALA–PDT with 417-nm blue light. 20% not Further PDT parameters were reported Comparator 2 See 2nd comparator 3-hr incubation: above Treatment details Treatment Not Not stated Population details Population intention Treatment Curative of lesion Type(s) and histology Non- AK hypertrophic Main eligibility criteria Patients with non- at least four AK and hypertrophic diffuse photodamage Patient characteristics stated Concomitant treatment mth et al. et al. RCT Day 1, then at 1, Day Not stated 39 wk, and 1 5 wk, Study details Abstract Data source Country USA English Language Study design of participants No. 18 Total: Not stated Intervention: Not stated Comparator: Not 2nd Comparator: stated of recruiting No. centres 1 Follow-up period and Follow-up frequency (2003) 212 Authors Touma 213

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Treating Treating This Authors’ conclusions field cancerisation in organ transplant with topical MAL–PDT recipients well is efficacious and generally tolerated (further conclusions relating AK reported) of to prevention Brief study appraisal intended study was primarily PDT in prophylactic to evaluate patients and this immunosuppressed details Few should be borne in mind. about concealment provided were and blinding was not of allocation, was not treatment The control used. differences and intercentre predefined impacted on the to have likely are were figures (of which few results study, As a comparative provided). with should be considered the results not be reliable caution and may Interpretation 0.001). At 0.001). wk (erythema, wk (erythema, < mth: MAL–PDT mth: mth were similar in both mth were -value reported). Lesion p -value reported). Cosmetic outcomes were Cosmetic outcomes were Local AEs associated with Local mth, more hypopigmentation hypopigmentation more mth, mth: MAL–PDT 77% and control MAL–PDT 77% and control mth: This trial aimed to treat This trial aimed to treat Morbidity existing lesions and also prevent rates response Only recurrence. been and cosmetic outcomes have Lesion CR rate at reported here. 3 74% (no rate at 15 response 89% 88% and control lesions that rates for Recurrence at baseline and rated present were 3 as CR by (PDT 24% and 20% control) groups with no significant difference to normal QoL and return activity on a 3-point the investigator rated by MAL–PDT resulted Overall scale. outcomes favourable in more for treatments than the control ( p hypopigmentation 15 group was reported in the control was and obvious hypopigmentation 0% (MAL–PDT) vs 25% (control). found was No significant difference scar formation for groups between AEs 75% of reported by MAL–PDT were transient patients although most were within 1 and resolved 6% of patients pain and crusting). MAL–PDT due to pain; discontinued in 17 out pain was judged as severe sessions but most of 420 treatment of moderate pain. reported were AEs in the 48% of patients reported erythema, including pain, area control crusting or blistering of mild to moderate intensity Results ). ). 2 mth J/cm wk treatment area area treatment wk after 2 MAL–PDT vs hr with an occlusive hr with an occlusive mg/g cream applied in applied mg/g cream nm, light dose 37 nm, mth later. Any visible lesions at 21 Any mth later. mth for a total of five treatments. treatments. a total of five mth for Patients’ eyes were protected during protected were Patients’ eyes Fans and cold water treatment. all patients to used for were spraying minimise pain was area Comparator Control discretion at the investigator’s treated in suitable therapy utilising any with normal clinical accordance or practice EXCEPT 5-FU cream was Treatment imiquimod cream. 9 and out at baseline and 3, carried 15 to according treated or 27 mth were Control preference. the investigator’s (83%) cryotherapy utilised: treatments and cauterycurettage (4%) laser (2%) surgery (1%) therapy Treatment details Treatment and covered for 3 for and covered was removed Excess cream dressing. illuminated with saline and the area a light from red with non-coherent lamp (630 Trial treatments treatments Trial choice of treatment investigator’s (within-participant comparison) 2 Intervention MAL–PDT: 1 given, were treatments apart (baseline and 1 single Additional randomisation). 9 and at 3, given were treatments 15 visible lesions at 21 and 27 Any at the investigators’ treated were prepared Lesions were discretion. to debride the using a small curette MAL 160 area. to 50-cm 1-mm layer mm in Not yr 10 Organ yr and had Curative. Curative. yr prior to yr) with the contralateral 2 yr yr between two and 10 lesions in two and 10 lesions in two two between symmetrical 50-cm Population details Population intention Treatment existing This trial aimed to treat recurrence. lesions and also prevent rates and cosmetic response Only been reported here outcomes have of lesion and histology Type(s) AK (some BCC and SCC in situ included but data not reported) Main eligibility criteria who had transplant recipients immunosuppressive received than 3 more for therapy areas on the face, scalp, neck, trunk or neck, scalp, on the face, areas required All patients were extremities. at least one previous received to have Exclusion the lesions. for treatment reported criteria were characteristics Patient 68 % Male: 30–78 Age range: 57 Median age: Most patients had Fitzpatrick skin organ transplantation types I–III, 3 and 34 between occurred (median 16 previously than 10 majority more areas Selected treatment treatment. scalp or on the face, mostly were grade I mostly AKs were extremities. ≤ or II and almost all were diameter Concomitant treatment stated RCT 176–178 11 59 mth after initial Authors et al. Wennberg (2008) Follow-up period Follow-up and frequency 21 and 15, 9, 3, 27 212 Study details Linked publications Full Data source published paper Country Not ‘Europe’ stated, English Language Study design of No. participants 81 (889 Total: AK) 90% lesions, 476 Intervention: lesions 413 Comparator: lesions of recruiting No. centres treatment 213

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 13 This was yr before the yr before Interpretation Authors’ conclusions activation Continuous PDT using daylight was as exposure and as, effective better tolerated than, PDT conventional Brief study appraisal well a generally conducted but small study and the results to be likely appear It should reliable. be noted though that six patients had received previously PDT in the treated (although more areas than 1 and that the study), LED illumination time stated was not clearly 0.50 for 0.50 for = Eighteen 0.0001). In the LED 0.0001). < 0.13 for percentage, p percentage, 0.13 for mth the absolute decrease in the mth the absolute decrease = 0.14). Both areas developed erythema developed Both areas 0.14). = hr after LED treatment were not significantly not significantly were hr after LED treatment Analyses based on 24 patients: The daylight areas areas The daylight based on 24 patients: Analyses Results At 3 Morbidity to baseline of lesions compared mean number vs 8.4 (79%) in the was 8.0 (71%) in the LED areas ( p areas daylight treatment, the daylight patients (62%) preferred and six (21%) had no (14%) LED treatment, four preference AEs VAS scale less painful on a 10-point significantly were 2.0 (mean maximal pain score, than the LED areas p LED, vs 6.7 for daylight for to 15 patients needed cold water spray light group, and one-half of these patients pain tolerable, make In two during illumination. breaks needed one or two were so treatments patients this was not enough, Pain of illumination time. stopped after one-third 6 scores vs 1.3 daylight of 1 for (mean maximal score different p LED, for mean number) to normal activity QoL and return most AEs were These and crusting after treatment. in in 10 patients (42%), area in the daylight severe was no patients (21%) and there in five the LED area in nine patients (38%) the areas between difference 2 cm (effective (effective 2 , peak irradiance peak irradiance , J/cm 2 MAL–PDT with , patients treated in patients treated , , mean effective red red mean effective , 2 2 J/cm J/cm J/cm nm) after covering the daylight the daylight nm) after covering hr outside in daylight (mean effective (mean effective hr outside in daylight min indoors, the daylight area had the area the daylight min indoors, g of MAL cream was applied to each was applied g of MAL cream Treatment details Treatment treatments Trial LED vs MAL–PDT with red daylight (within-participant comparison) Before Intervention PDT with daylight: graded, counted, lesions were treatment, AK lesions and photographed. mapped, into two marked of face or scalp were (~80 areas symmetrical treatment at 632 with light-impermeable area treatment rubber See LED: Comparator PDT with red above each) and scales and hyperkeratoses each) and scales hyperkeratoses Around using a curette. removed were 1 and with a dressing and covered area Following light-impermeable lead rubber. 30 and patients spent removed dressing 2.5 total dose 43 light dose 1.9 red light dose 1.2 red period between July and September), and September), July period between from MAL cream to have returning before The area removed. areas both treatment LED light was treated randomised to red with a light dose of 37 Curative yr yr Population details Population intention Treatment of lesion and Type(s) histology AK Main eligibility criteria AKs symmetrically Patients with distributed on the face or scalp. or lactating women Pregnant excluded were characteristics Patient 79 % Male: 63–90 Age range: 78 Mean age: with grade I, Most lesions were grade II and very a third around grade III were small number Concomitant treatment not exposed areas for Sunscreen treatment by covered FU RCT One 53 d (AEs) and mth (CR) Study details Full Data source published paper Country Denmark English Language Study design of No. participants 30 (29 Total: treated) 30 (29 Intervention: treated) 30 (29 Comparator: treated) of recruiting No. centres 3 Follow-up period Follow-up and frequency at 1–3 214 Authors Wiegell et (2008) al. DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT The authors compared overall pain overall authors compared AEs in a small sample, and scores, with those seen in conventional but using a comparator PDT, PDT of conventional treatment been have in this study would This informative. more much minimal abstract also featured reporting of methods and results Interpretation Authors’ conclusions activation will using daylight time more AK treatment make and more and cost-effective, the patient for convenient Brief study appraisal mth, there was there mth, 0.37 = Not assessed Erythema and crusting no significant difference in CR no significant difference vs 80% in rate (77% in 16% area p 8% area), Results At 3 Morbidity to normal QoL and return activity AEs (and treatments both in occurred similar to inflammation were PDT). seen after conventional used but not Pain diaries were intervention reported by arm PDT with min). Light exposure was Light exposure min). min outdoors (range Treatment details Treatment treatments Trial 8% MAL vs PDT with 16% (within-participant comparison) Intervention PDT 8% MAL: both given Patients were randomised to two treatments, was one area symmetric areas, and the 8% MAL cream given Patients other 16% MAL cream. sent home and instructed were time as to spend as much in daylight. possible outside, Patients spent an average of 210 62–372 using an electronic measured dosimeter watch Comparator PDT 16% MAL: See above Not Patients Not stated Curative stated Population details Population of lesion and histology Type(s) AK Main eligibility criteria Concomitant treatment Treatment intention Treatment AK of the face and scalp with characteristics Patient 40 Not mth RCT FU at 3 et al. (2008) Authors Wiegell et al. Study details Abstract Data source Country Denmark e English Languag Study design of participants No. 29 Total: 29 Intervention: 29 Comparator: centres of recruiting No. stated period and Follow-up frequency 215

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Appendix 14 Bowen’s disease data extraction

217

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 14 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 ALA–PDT This was a Interpretation Authors’ conclusions option the best treatment offer may This study shows disease. Bowen’s for the potential of light fractionation for of the disease to enhancing the response a ALA–PDT and illustrates the need for trial to determine powered suitably larger, significant is statistically if the effect Brief study appraisal small trial with unclear methods of Treatment randomisation and blinding. reported but not all methods were This study shows detailed. outcomes were the potential of PDT and its enhancement need light fractionation but would through in an as the authors state, confirmation, trial powered adequately

mth. In the twofold-illumination In the twofold-illumination mth. All patients in both groups All patients in both groups Results Not assessed AEs experienced some discomfort during No but all finished therapy. treatment In the seen in either group. SAEs were none of the single-illumination group patients complained of pain during In the twofold-illumination treatment. patients complained about pain five group Lidocaine of six patches. in the treatment was used in four without adrenaline patches Morbidity In the single illumination CR was seen in 22 patches (80%) group, at 12 CR was seen in 22 patches (88%) group a 3-wk maximum Patients reported (NS). which was not different healing time, treatments between to normal activity QoL and return cm. cm. , , 2 J/cm hr after ALA hr after ALA–PDT using a hr with a margin of 1 2 2 J/cm hr after ALA application at a ALA application hr after nm, 4 nm, mW/cm Treatment details Treatment Further PDT parameters were not Further PDT parameters were reported As illumination: Twofold Comparator single illumination except patches for 4 and 6 light treated were application at doses of 20 and 80 application respectively, separated by a 2-hr dark separated by respectively, at Each illumination was delivered interval. 50 A diode laser and light emitting of illumination at a wavelength provided 630 Trial treatments treatments Trial ALA–PDT with a single illumination vs illumination twofold Surface Intervention Single Illumination: ALA, 20% removed. scale or crusts were and topically was applied produced, locally 4 left in place for dose of 75 yr yr Lidocaine, Lidocaine, mm) mm (range Population details Population Type(s) of lesion Type(s) and histology disease Bowen’s Main eligibility criteria Not stated Patient characteristics 43 % Male: 49–91 Age range: 74 Mean age: Mean lesion diameter: 14.5 5–40 12, Trunk Locations: hand leg 11, lower upper leg 4, ear 7, 8, cheek and/or nose 3, frontal arm 1, 2, eyelid and/or temporal area scalp 1 1, The sample included organ recipients seven Concomitant treatment 2% without adrenaline 2% without adrenaline was used if patients it required wk, wk, et 4 RCT mth intervals One 69 mth Study details (2007) al. Full Data source published paper The Country Netherlands English Language Study design of participants No. 40 (50 Bowen’s Total: disease patches) 25 Intervention: lesions (participant no. not stated) 25 Comparator: lesions (participant no. not stated) of recruiting No. centres then at 3 up to 28 Follow-up period Follow-up and frequency 218 Authors de Haas 219

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 14 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 A single course There was a There Authors’ conclusions treatment of verteporfin PDT showed multiple non- for patients with benefit melanoma skin cancers Brief study appraisal on issues such as lack of information blinding and allocation concealment, many and the authors did not present and population details by results difficult to It is therefore diagnosis. conclusions about the reliable any make verteporfin in patients with efficacy of particularly as they disease, Bowen’s of the overall a small proportion formed of lesions number Interpretation

2 , , 2 J/cm J/cm , and 50% at 180 , 2 mth, the mth, J/cm Assessed but not reported for for Assessed but not reported 100% at 120 At 6 Morbidity no (i.e. histopathological response tumour) was 85% at 60 residual Assessed but not reported for Bowen’s Bowen’s for Assessed but not reported group AEs group Bowen’s QoL and return to normal activity QoL and return Results 2 : : 2 vs hr 2 J/cm : See : 2 J/cm : : J/cm 2 of 2 J/cm J/cm J/cm mm around the mm around PDT at 60 nm) from a non- nm) from . Tumours re-treated at re-treated Tumours . vs PDT at 180 2 2 10 ± ) J/cm 2 verteporfin followed 1–3 followed verteporfin mW/cm 2 40 mg/m ± min intravenous infusion of min intravenous mg/m mth if necessary (with dose increased 10 14 3 to 18 See above red light (688 red The exposed area thermal LED panel. had a margin of 3–4 was delivered The irradiance lesion. 200 later by exposure to 60 exposure later by Intervention PDT at 60 PDT at 120 Comparator PDT at 120 Treatment details Treatment treatments Trial above 2nd comparator PDT at 180 Not Oral Population details Population of lesion and Type(s) histology Superficial 277 lesions (66%); BCC, 93 lesions nBCC, disease, Bowen’s (22%); BCC 34 lesions (8%); unspecified 17 lesions (4%) Main eligibility criteria Patients with biopsy- at least two superficial or proven nBCC or Bowen’s lesions Patient characteristics Bowen’s stated for group Concomitant treatment pain analgesics for 68 RCT mth wk, and 3, 6, 6, and 3, wk, 6 Four Study details Full Data source published paper USA Countries Canada, English Language Study design of participants No. Not stated by Total: diagnosis (34 lesions) Not stated Intervention: diagnosis (27 lesions) by Not stated Comparator: diagnosis (one lesion) by Not 2nd Comparator: diagnosis (six stated by lesions) of recruiting No. centres et al. (2004) Authors Lui et al. period and Follow-up frequency 18 and 24 12, 218 219

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 14 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Interpretation Authors’ conclusions light is less Green light in than red effective of Bowen’s the treatment ALA–PDT disease by Brief study appraisal with A small study, unclear methods of allocation randomisation, concealment and blinding of outcome assessors No 0.002). A high 0.002). = 0.13 (95% CI 0.04 to = No ulceration or infection complicating No ulceration or infection Results In the red light group 24 lesions light group Morbidity In the red and a further one treatment following cleared giving an initial treatment six after a repeat Eighteen lesions treated rate of 94%. response after one treatment light cleared using green giving an with a furtherclearing on repeat three in response Difference of 72%. initial response significant ( p was statistically at 1yr in evident obvious scars were clinically either group AEs were and no photosensitivity reactions therapy in either documented after PDT treatment in pain was seen No significant difference group. light No red groups. the treatment between lesions two patients needed anaesthesia whereas light group in the green (one patient) treated needed anaesthesia Four both types of light. patients received Twelve six light was the most painful, stated that green while two light was the most painful, that red the light patients could not distinguish between used recurrence rate was observed in the green light rate was observed in the green recurrence in comparison recurrences with seven group after PDT with red lesions relapsing with two recurrence OR for light. 0.48) to normal activity QoL and return mth if lesions 2 nm for red red nm for mW/cm 15 ± of cream of cream 2 h pre-illumination. h pre-illumination. nm was used to 15 ALA–PDT with red light ALA–PDT with red mm. The cream was kept was kept The cream mm. ± mg/cm of red light of red 2 of light 2 J/cm J/cm A repeat treatment was given after 2 was given treatment A repeat necessary light except a red As for Comparator of 540 wavelength 62.5 deliver was applied to cover the entire field of the entire to cover was applied disease-free including a clinically illumination, margin of at least 4 dressing in place under an occlusive short ‘Paterson’ lamp with 300W xenon A plasma discharge was adjusted using arc filters to 630 appropriate At a fluence rate of 86 light. received 125 received Treatment details Treatment treatments Trial light ALA–PDT with green vs Surface crusts were Intervention Red light: abraded. and the surface was gently removed was ALA in an oil-in-water emulsion Topical to the lesions 4 applied 50 Approximately

yr yr Local mm in diameter. No mm in diameter. Population details Population of lesion and Type(s) histology Bowen’s disease Main eligibility criteria disease Biopsy-proven with individual lesions of ≤21 lesion had been previously treated characteristics Patient 50–87 Age range: 73 Mean age: of lesions per patient No. one and varied between six (median three) Concomitant treatment anaesthetic (1% plain intradermal lidocaine by injection) was offered during PDT treatment mth After RCT Not stated 70 Study details Full Data source published paper Country UK English Language Study design of participants No. 19 (70 lesions) Total: randomised 16 (61 up lesions) followed 32 lesions Intervention: (no of patients not specified) 29 lesions Comparator: (no of patients not specified) of recruiting No. centres Follow-up period Follow-up and frequency all patients clearance, at monthly reviewed were up to 12 intervals, 220 Authors Morton et al. (2000) 221

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 14 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Interpretation Authors’ conclusions PDT is at least as effective in the as cryotherapy of Bowen’s treatment disease and was associated AEs in this study with fewer rate recurrence and a lower Brief study appraisal This was a small trial using lamp as a a prototype Results were light source. lesion rather reported by By chance patient. than by significantly lesions were but larger in the PDT group into account this was taken when assessing clearance of the trial The results rates. but would promising are confirmation in require larger trials Visible mth). CR rate mth). 0.01). Free from pain from Free 0.01). = p mth and 8 0.01). Recurrence Rate during Recurrence 0.01). < mth following clearance (no. of clearance (no. mth following Pain during treatment (no. of lesions): PDT, PDT, of lesions): (no. Pain during treatment d following treatment (no. of lesions): PDT of lesions): (no. treatment d following Results was, therefore, 100% for PDT and 90% for PDT and 90% for 100% for therefore, was, cryotherapy to normal activity QoL and return 12 scarring four cryotherapy PDT zero, lesions): AEs 12 mild cryotherapy, moderate; six mild and five moderate ( and seven 10 10 cryotherapy 15; both treatments, All six patients who received reported PDT as lesions, multiple due to having PDT zero; of lesions): Blistering (no. less painful. of lesions): Ulceration (no. seven. cryotherapy Secondary infection five. cryotherapy PDT zero; No two. cryotherapy PDT zero; of lesions): (no. after PDT occurred photosensitivity reactions Morbidity 15 of 20 PDT, Clearance after one treatment: 10 of 20 lesions cryotherapy, lesions; five PDT, treatments: Clearance after two six lesions cryotherapy, lesions; remaining lesions in the cryotherapy four The remaining was There treatment. a third required group the two between no significant difference by However, in clearance rates. treatments overall PDT were by chance lesions treated In group. larger than those in the cryotherapy model taking size of lesion a linear regression that a lesion of any the probability into account, at the 1st treatment cleared size is completely with PDT than greater was significantly ( p cryotherapy 12-mth following clinical clearance: PDT zero; PDT zero; clinical clearance: 12-mth following (6 two cryotherapy of 2 W min, min, mg/cm mm rim of nm. To broaden broaden To nm. . Following therapy, therapy, Following . 2 s. A single freeze–thaw A single freeze–thaw s. J/cm PDT with ALA vs Cryotherapy vs ALA with PDT mm in diameter, at a fluence rate mm in diameter, and a treatment time of 30 and a treatment 2 21 ≤ mW/cm Treatment details Treatment treatments Trial Surface crusts were Intervention PDT: abraded prior and the surface gently removed with topical 5-ALA in an oil-in- to application 50 Approximately 20%. water emulsion lesions received 125 lesions received 3-mm punch biopsies were performed in lesions performed 3-mm punch biopsies were clinical clearance or was doubt over there where administered were Repeat treatments recurrence. if lesions persisted Liquid nitrogen Comparator Cryotherapy: to lesions via a hand-held Cry-Acwas applied the freeze formation, After initial ice field spray. 20 was maintained for cycle technique was used with a 2–3 tissue included in the treatment healthy clinically 3-mm punch biopsies therapy, Following field. was there in lesions where performed were clinical clearance or recurrence. doubt over if lesions administered were Repeat treatments persisted the treatment field and to produce uniform uniform field and to produce the treatment a 25-mm collimating of the lesions, irradiation bundle. lens was attached to the 5-mm fibre lesions in at least a 10% margin around Allowing permitted the treatment the field of irradiation of lesions of 70 xenon short arc plasma discharge producing a plasma discharge producing short arc xenon flat spectral output broadband wave continuous Using filters, visible spectrum. the entire across the spectral output of lamp was adjusted to about 630 a 30-nm bandwidth, cream was applied to cover the entire irradiation irradiation the entire to cover was applied cream margin. disease-free field including the clinically in place under an occlusive was kept The cream dressing illuminated with a hours later lesions were Four The lamp incorporated a 300 lamp. prototype yr yr Patients mm in diameter. mm in diameter. 21 Population details Population Main eligibility criteria Histological confirmation of with Bowen’s individual lesions ≤ No lesion had been treated previously Patient characteristics 16 % Male: 62–88 Age range: 76 Mean age: of Location and no. face legs 33, lesions: hand two five, Concomitant treatment local offered were anaesthetic (1% plain lidocaine by intradermal injection) during treatment 179 d and 2 mth for mth for RCT Not stated 71 d for AEs. 2-monthly 2-monthly AEs. d for et al. Authors Morton et al. (1996) Follow-up period Follow-up and frequency No. of participants No. 19 (40 lesions) Total: 20 lesions, Intervention: not participant no. stated 20 lesions, Comparator: not participant no. stated of recruiting No. centres Study details publications Linked Full Data source published paper Country UK English Language Study design AEs and late recurrence 220 10 intervals clinical for Following response. 2-monthly clearance, intervals 12 for 221

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 14 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 MAL–PDT The Interpretation Authors’ conclusions option treatment is an effective disease with excellent Bowen’s for cosmetic outcome Brief study appraisal authors’ conclusions appear although mitigating appropriate, factors include the fact that 11% excluded lesions were of treated population, the per-protocol from on methods the lack of reporting of randomisation and allocation and the possibility concealment, and of institutional differences in (40 centres deviation protocol results 11 countries) affecting mth mth: PDT, PDT, mth: 1.77 to 1.01, 1.77 to 1.01, = mth: PDT, 77/82 (94%); 77/82 (94%); PDT, mth: Good or excellent cosmetic 1.73; 95% CI 1.03 to 2.93). 95% CI 1.03 to 2.93). 1.73; mth: PDT, 68%; placebo, 11%; 11%; placebo, 68%; PDT, mth: = SAEs: PDT, 6%, cryotherapy, 12%. 12%. cryotherapy, 6%, PDT, SAEs: mth: PDT, 80%; Placebo, not Placebo, 80%; PDT, mth: Results AEs deaths) were SAEs (including four placebo patients; four PDT, reported. cryotherapy, patients; two cream, patients three Morbidity CR rate at 3 4/19 (21%); Placebo, 103/111 (93%); and 5-FU 73/85 (86%), Cryotherapy, 12-mth recurrence (83%). 24/29, not stated; Placebo, 15%; PDT, rate: 21%. 24% and 5-FU, Cryotherapy, Estimated sustained CR rate at 12 69%. 5-FU, 67%; cryotherapy, stated; significant was a statistically There MAL–PDT between difference therapy and combined standard (OR different MAL–PDT was significantly (OR cryotherapy from Estimated sustained CR rate 3.12). at 24 59% 5-FU, 60%; cryotherapy, to normal QoL and return activity outcome at 3 16/21 5-FU, 43/65 (66%); cryotherapy, This was maintained at 12 (76%). nm, light nm, wk were re- wk were wk, once daily during once daily wk, wk were re-treated wk were MAL–PDT vs Placebo PDT . Mean illumination time was . 2 wk were re-treated wk were re-treated wk were s. Mean total freezing time was Mean total freezing s. mg/g of topical MAL cream was mg/g of topical MAL cream J/cm s. Treatment was repeated once after was repeated Treatment s. hr then was washed off with 0.9% saline min 37 s dose was 75 Treatment details Treatment treatments Trial vs 5-FU vs Cryotherapy Lesions were Intervention MAL–PDT: gentle surface debridement with by prepared 160 a curette. on the skin It remained to the lesions. applied 3 for illumination with non-coherent solution before was 570–670 Wavelength light. red 10 Lesions cycle. a complete treatment 1 wk for with a PR at 12 MAL– As for Comparator Placebo cream: Lesions with a PR at 12 PDT. treated A handheld 2nd comparator Cryotherapy: was used in a single spray liquid nitrogen After an initial ice field cycle. freeze–thaw healthy with a 2-mm rim of clinically formation for a the ice field was maintained tissue, of 20 minimum 25 Lesions with a PR at 12 5% 5-FU Topical comparator 5-FU: 3rd 4 for was applied cream Mean thereafter. and twice daily the 1st week, was 42 and 45 in the of applications number Lesions respectively. 1st and 2nd treatments, with a PR at 12

mth mm yr mm in yr yr or older with mth or that were strongly strongly mth or that were Population details Population Type(s) of lesion and Type(s) disease histology Bowen’s Main eligibility criteria Patients Inclusion criteria: 18 confirmed histologically diagnosis of SCC in situ a biopsy specimen from within the last 5 taken of and with no evidence change in appearance any of lesion suggestive progression Lesions that had been within the previous treated 3 less than 6 pigmented, than 40 or more diameter or located on the excluded genitalia were characteristics Patient patients: the treated For 39 % Male: 39–99 Age range: 73 Mean age: of Location of lesion (no. face (scalp) 68, lesions): extremities trunk 34, neck, 173 Concomitant treatment Not stated 180–184 3, 12 3, RCT 40 mth after last 73 Study details publications Linked Full Data source published paper Countries Not stated, countries 11 European English Language Study design of participants No. 229 randomised, Total: (275 225 treated lesions) 96 (124 Intervention: lesions) 17 (24 Comparator: lesions) 82 (91 2nd Comparator: lesions) 30 (36 Comparator: 3rd lesions) of recruiting No. centres Follow-up period Follow-up and frequency and 24 222 Authors Morton et al. (2006) treatment 223

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 14 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 hr PDT delivered PDT delivered This trial Authors’ conclusions as fractionated illumination with 16 a 2-hr of incubation separated by dark interval improves significantly outcome in tumour therapeutic eradication Brief study appraisal of patients a small number had only Procedures disease. with Bowen’s of randomisation and blinding No unclear. outcome assessors were Although provided. patient details were fractionated receiving the group the illumination had better outcomes, contribution of the longer relative incubation time and the fractionated It is also unclear if unclear. delivery are AEs any were there Interpretation Not wk, wk, Not assessed At 24 wk, At 24 wk, Morbidity tumour was residual of six in four found (67%) biopsied patients in the single-illumination, shorter-incubation was Treatment group. At 24 repeated. there was persistence of there of nine tumour in two (22%) biopsied patients in the fractionated, longer incubation group to QoL and return normal activity assessed AEs Results wk . There There . 2 . Spraying of Spraying . 2 was delivered was delivered mW/cm 2 was delivered in two in two was delivered 2 J/cm mW/cm J/cm cm of the surrounding cm of the surrounding hr incubation with ALA cream and ALA cream hr incubation with nm) was applied. 100 nm) was applied. ALA–PDT with 16-hr incubation and two ALA–PDT with 16-hr incubation and two with a fluence intensity of 30 hr 2 wk after illumination in patients with fluorescence wk after illumination in patients with fluorescence J/cm nm) was applied. The total of 100 nm) was applied. mm, covering the treated area and 1 area the treated covering mm, doses of 50 was a 2-hr break between illuminations. Spraying of water and Spraying illuminations. between was a 2-hr break After the cooling with fan was done to minimise pain sensations. next the for recommended were ointments sunblock treatments Biopsies were measures. to sun protection in addition days few 24 performed detected after 4 Comparator PDT with 5 the illumination was as for for Preparation single light fraction: was then a 5-hr incubation period There intervention group. light (635 red before in one dose, with a fluence intensity of 30 in one dose, water and cooling with fans, and sun protection measures were were measures and sun protection water and cooling with fans, 24 performed Biopsies were the intervention group. as for after 3-hr after illumination in patients whom fluorescence ALA was detected incubation with Treatment details Treatment treatments Trial ALA–PDT with 5-hr incubation and a single light fractions vs illumination light ALA–PDT with 16-hr incubation and two Intervention with ointments (and 1st removed Thick crusts were fractions: the with a saline solution, After cleaning the area dressings). wet to a thickness of approximately was applied ALA cream 20% 1 Aluminium dressing. occlusive by was covered The area skin. ambient skin from to protect was placed on top in order foil light red was then a 16-hr incubation period before There light. (635 Not Curative Population details Population Treatment intention of lesion Type(s) and histology disease Bowen’s Main eligibility criteria Previous histologically confirmed diagnosis of disease Bowen’s Patient characteristics stated 57 RCT One wk Authors Puizina- (2008) Ivic et al. Follow-up period Follow-up and frequency 24 No. of No. participants 15 Total: Nine Intervention: Six Comparator: of recruiting No. centres 222 Study details Full Data source published paper Country Croatia English Language Study design 223

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 14 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Topical Topical Interpretation Authors’ conclusions than effective ALA–PDT is more topical 5-FU in the treatment disease with fewer of Bowen’s ALA should be considered AEs. one of the 1st-line therapeutic disease Bowen’s options for Brief study appraisal Methods of randomisation, allocation concealment and blinding of outcome assessors This study, not described. were highlights the although small, Bowen’s potential of PDT for should be disease but results confirmed in further trials mth). mth). 0.01). 0.01). = mth). There were six were There mth). Not assessed 0.006) = mth FU there were two two were mth FU there mth) in the PDT group was 27 of 33 mth) in the PDT group mth at any PDT treatment site. 10 of 15 site. PDT treatment mth at any hr in four. Mild discomfort was reported by the Mild discomfort by was reported hr in four. d (mean 21). In assessment of intensity and duration d (mean 21). 4.78 (95% CI 1.56 to 14.62, p 4.78 (95% CI 1.56 to 14.62, Three patients with five lesions from the 5-FU group the 5-FU group lesions from patients with five Three = Results 29 of 33 lesions (88%) showed initial complete Morbidity 29 of 33 lesions (88%) showed remaining clinical clearance with PDT a PR in the four 22 of 33 lesions (67%) had complete clinical clearance lesions. prior withdrawn lesions were Five after 5-FU and six had PR. After adjustment to completion of a single cycle 5-FU. the difference response, the influence of lesion size on for At 12 in clearance rates was NS. (at 6 and 7 in the PDT group recurrences 11 and 2 at 12 8, 7, (at 5, in the 5-FU group recurrences (48%). lesions (82%) vs 16 of 33 in the 5-FU group OR AEs the treated over dermatitic reactions widespread developed Another patient the study. from withdrawn limbs and were had widespread the 5-FU group lesions from with two the treatment. but elected to continue dermatitic reactions developed lesions ulcerated and two three In the 5-FU group, The cycle. on completion of the treatment painful erosions There scarring. prominent ulcerated lesions healed leaving obvious and no clinically in the PDT group no reactions were at 12 scar formation and 14 of 19 in the PDT group patients in the 5-FU group During PDT pain cycle. reported pain during the treatment ‘severe’ six and ‘moderate’ by six patients, ‘mild’ by was rated illumination in 4 patients and Pain settled following two. by persisted to 24 In the 5-FU six patients lasting 7–42 d (mean 14). remaining two ‘moderate’ by six patients, ‘mild’ by pain was rated group Discomfort persisted in the 5-FU group two. by ‘severe’ and 7–42 for ( p in the 5-FU group pain was found more of pain, no statistically time revealed Comparison of total pain over the between in the median pain scores significant difference groups two Overall clearance (at 12 Overall to normal activity QoL and return PDT vs 5-FU mW/cm wk and PDT was nm). The time of nm). min. All patients were All patients were min. J/cm squared with a J/cm squared 15 ± Treatment details Treatment ALA in Intervention 20% was an oil-in-water emulsion to lesions including applied a 5-mm margin of clinically PDT. normal skin 4-hr before Illumination was with a 300- lamp at a dose W xenon of 100 Trial treatments treatments Trial density of 50–90 light red narrowband squared (630 illumination was dependent on lesion size and ranged from 12 to 40 Further if required. repeated not PDT parameters were reported Comparator 5-FU (Efudix) to the lesions thinly was applied during wk 1 once daily initially (wk 2–4). and then twice daily at reviewed All patients were if 6wk and 5-FU was repeated required reviewed at 6 reviewed yr cm yr Local Population details Population Type(s) of lesion and Type(s) histology Bowen’s disease Main eligibility criteria Patients with 1–3 lesions of previously histologically untreated, disease Bowen’s proven measuring 0.5–4 Patient characteristics 20 % Male: 65–88 Age range: 76 Mean age: arms Legs 58, Lesion site: face 4 4, Patients had between lesions one and three of skin types and were I–III Concomitant treatment anaesthetic (1% plain intradermal lidocaine by injection) was offered to patients experiencing pain during PDT treatment 185 Two 72 mth Authors Salim et (2003) al. Study details Linked Publications Full Data source published paper Country UK English Language Study design RCT of No. participants 40 Total: 20 (33 Intervention: lesions) 20 Comparator: (33 lesions) of recruiting No. centres 224 period Follow-up and frequency 12 225

Appendix 15 Basal cell carcinoma data extraction

224 225

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 This Overall Overall yr as well yr as well Interpretation Authors’ conclusions study demonstrated that lesion rate with MAL–PDT recurrence was comparable to treatment cryotherapy thaw double freeze of superficial BCC treatment for a better cosmetic and provided outcome Brief study appraisal conducted this trial was well The lack of reported. clearly calculation means a power was it is unclear if there the between no difference or if the study was treatments, to detect such a underpowered This trial did include difference. a long term FU of 5 efficacy as examination of safety, and cosmetic outcomes mth were 32% in mth were mth: 30% of PDT mth: 0.86 yr 3 = Cosmetic outcome mth and 5 0.00078) = mth 0.90). Cumulative recurrence rate after 5 recurrence Cumulative 0.90). = 0.0005) = AEs were reported by 73% (44/60) PDT patients and 79% reported by AEs were 0.49) mth (105 patients): Fewer lesions recurred with MAL–PDT lesions recurred Fewer mth (105 patients): of lesions in CR was 66% for Proportion mth (107 patients): mth (115 patients): Lesions with inCR after 3 mth (115 patients): ‘excellent’ outcome compared 60% of PDT patients had an yr: = Results patients had an ‘excellent’ outcome compared with 4% for with 4% for ‘excellent’ outcome compared patients had an ( p cryotherapy Morbidity 3 CR rates did group. and 30% in the cryotherapy the PDT group 95%, 97% vs cryotherapy: (PDT: the groups between not differ p 12 patients had an (8% vs 16%) More than with cryotherapy cosmetic outcome with MAL–PDT than ‘excellent/good’ at 3 and 12 cryotherapy 36 74% estimated CR (NS). cryotherapy MAL–PDT and 67% for The population. to per-protocol according rate in both groups rates in lesions with CR 3 mth after the last lesion recurrence cryotherapy MAL–PDT and 20% for 23% for were treatment as physicians cosmetic outcome was rated by The overall 89% of the MAL–PDT patients and 63% for ‘good’ ‘excellent’ or patients of the cryotherapy 75% vs (PDT: the groups between CR rates did not differ 5 yr: p 74%, cryotherapy: p 20%, 22% and cryotherapy: yr was PDT: to normal activity QoL and return was better with PDT at both 3 5 ( p cryotherapy with 16% for All cosmetic outcomes rated by investigators using a 4-point investigators All cosmetic outcomes rated by scale AEs local and transient, AEs were Most patients. (46/58) cryotherapy AEs of treatment-related as a result no patients discontinued 33% cryotherapy 37% PDT, Pain: 47% cryotherapy 35% PDT, Crusting: 21% cryotherapy 30% PDT, Erythema: 80% PDT 73% cryotherapy Mild: 25% cryotherapy 13% PDT, Moderate: 1% cryotherapy 5% PDT, Severe: hr. The hr. J/cm. J/cm. d apart) mm nm) MAL–PDT mm of mg/g, was mg/g, Treatment details Treatment Trial treatments treatments Trial vs Cryotherapy A Intervention MAL–PDT: was initially single treatment prepared Lesions were given. surface debridement. by 160 MAL cream, applied in a layer of 1 in a layer applied to the lesion and 5 surrounding tissue for 3 for tissue surrounding cream was washed off using a cream saline solution and the treated was then illuminated area light red with non-coherent 570–670 (wavelength In patients with incomplete was CR at 3-mth treatment consecutive (two repeated MAL–PDT sessions 7 using a light dose of 75 Comparator Cryotherapy: was applied Cryotherapy cycles freeze–thaw in two spray using liquid nitrogen to the lesion and a applied of area 3-mm surrounding was Procedure tissue. healthy period after a thaw repeated times the to three of two In patients duration. freeze with an incomplete response was at 3-mth treatment (double freeze–thaw repeated cryotherapy) mm mm 30 Not 6 mm on neck/ mm on face/ 20 15 yr or older with Population details Population but < < scalp, or < extremities, Further on trunk. eligibility criteria were reported Patient characteristics stated Concomitant treatment Concomitant with treatment immunosuppressive medication was prohibited Treatment intention Treatment Curative of cancer Type(s) and histology Primary superficial BCC Main eligibility criteria Patients aged 18 up to 10 previously primaryuntreated superficial BCC lesions suitable for Diagnosis cryotherapy. confirmed using punch Lesions had to biopsy. diameter > have 79 3 RCT 186–190 13 across 13 across yr Authors Bassett- (2008) Seguin et al. Study details Linked publications Full Data source published paper Country Not stated English Language Study design (between-participant comparison) of participants No. 120 randomised, Total: (219 118 treated lesions) 58 60, Intervention: and analysed treated (103 lesions) 57 58, Comparator: and analysed treated (98 lesions) of recruiting No. centres 226 European seven countries period Follow-up and frequency 4 3, 2, then at 1, mth, and 5 227

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 There was no There This small pilot study was generally of high quality in its study was generally The absence of methods and reporting. before the PDT group anaesthetic for in explain the differences may curettage pain scores Authors’ conclusions in general, suggestion that PDT was, more PDT appears better than surgery. painful than surgery nBCCs. low-risk for Surgery the 1st treatment remains nBCCs choice for Brief study appraisal Interpretation

yr 0.001, and 0.001, = 0.24 = 0.42) or 10 non-medical = Median pain scores for the 1st for Median pain scores 0.23) 0.004, respectively). Both groups had Both groups respectively). 0.004, = = For the PDT group 13/21 the PDT group Morbidity For clear at 1 lesions (62%) were to 15/19 lesions (79%) in the compared p surgery group, persistent BCCs in five were There but none in the surgerythe PDT group (ns) group to normal activity QoL and return in mean scar was no difference There the (on a 1–4 scale) between severity by when judged independently groups PDT vs 2.1 10 non-medical men (1.9 for p surgery, for women (2.2 for PDT vs 2.5 for surgery, surgery, PDT vs 2.5 for (2.2 for women p AEs out of 10) both (scored BCC treated after and immediately during treatment, for the PDT group, five were treatment, surgery ( p and 0 for group p at later assessments of zero a score Results

2 mW/cm hr (under . PDT repeated PDT repeated . 2 ALA–PDT (following ALA–PDT (following J/cm mth if residual BCC was clinically BCC was clinically mth if residual and total dose 125 at 3 evident Comparator Excision with surgical the British by margins as recommended Scalpel Association of Dermatologists. infiltrative surgeryunder performed was lidocaine anaesthesia but surgical re- not conducted excisions were Treatment details Treatment treatments Trial vs Excision superficial curettage) surgery Intervention Initial 4-mm punch followed biopsy to assess tumour depth, (without superficial curettage by anaesthetic) and PDT with 630-nm laser 6 for ALA applied after 20% was 12 Irradiance occlusion). 2cm ≤ Not Curative Population details Population Treatment Treatment intention of cancer Type(s) and histology Nodular BCC Main eligibility criteria Non- adults (18 pregnant with well- or over) defined BCCs non- on anatomically critical sites were eligible Patients with or BCCs, recurrent BCCs at high-risk sites or patients with or immunodeficiency photosensitivity were excluded 100 % Male: Concomitant treatment stated mth. mth. wk 191 RCT FU to assess 87 (between-participant comparison) of participants No. 31 (40 lesions) Total: 18 (21 lesions) Intervention: 13 (19 lesions) Comparator: centres of recruiting No. One period and Follow-up frequency 6 and 12 at 3, response Study details publications Linked Full published Data source (letter) paper Country UK English Language Study design FU to assess pain at 3, 6, 24 6, FU to assess pain at 3, and 48 hr also at 1 226 et al. Authors Berroeta (2007) 227

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 There is a There Although Interpretation treatment methods were very well very well methods were treatment study design details on issues described, and blinding, such as randomisation, 154 or 155 patients (were dropouts making it not provided, were treated?) reliability of the difficult to assess the results Authors’ conclusions in the CR rate of significant increase fraction illumination PDT using two-light with a single- scheme compared illumination scheme Brief study appraisal yr, yr, 0.0002). 0.0002). = 0.002). The results The results 0.002). = Assessed but not reported 5/100 (5%) patients required 5/100 (5%) patients required Results 97% vs 89%, p 97% vs 89%, very similar when analysis were of on a subgroup was undertaken 10/262 BCCs. proven histologically (4%) lesions failed to respond, in the fractionated- or recurred, compared illumination group with 32/243 (13%) in the single- ( p illumination group Morbidity CR of lesions using greater was significantly fractionated illumination compared with single illumination (at 1 no significant were There within rates, in response differences the for each illumination group, used light sources different to normal QoL and return activity AEs in the single illumination pain relief to 15/55 (27%) compared group patients in the fractionated illumination group hr nm), with nm), wk apart) nm with a bandwidth ) delivered 4 and 6 ) delivered 2 mm. A light-protective A light-protective mm. Fractionated illumination m optical fibre and using a µ m optical fibre mW/cm (at 50 2 nm; or a 2nd broadband source with source or a 2nd broadband nm; J/cm mth were re-treated. Further parameters re-treated. mth were Treatment details Treatment after administration of 20% ALA ointment after administration of 20% (containing 2% lidocaine) with a 1-cm margin. were light sources different One of three used on each lesion (a 630-nm diode laser, coupled into a 600- fluence rate; uniform combination of lenses for a light-emitting diode 633 of 20 590 and 650 an output of between a margin of at least 5 was used bandage (including aluminium foil) the 2-hr dark interval between to provide instructed to stay Participants were fractions. out of the cold Comparator PDT with placebo cream: cycles (1 two Patients received was surface There PDT. of placebo cream debridement and slight lesion debulking prior BCC with partialat clinical response to PDT. 3 not reported were Trial treatments treatments Trial PDT vs single-illumination Intervention Fractionated illumination removed gently Crusts and scaling were PDT: ALA before using a disposable curette Illumination using doses of 20 and application. 80 Age yr yr Curative Population details Population Treatment Treatment intention of cancer Type(s) and histology Primary superficial BCC Main eligibility criteria Not stated Patient characteristics 31–83 range: 57 Mean age: All participants were Caucasians Concomitant treatment lidocaine Paracetamol, (without adrenaline) or bupivacaine if required . et al . yr RCT yr, maximum maximum yr, FU four times FU four One 83 Study details Full Data source published paper The Country Netherlands English Language Study design (between-participant comparison) of participants No. 154 (505 lesions) Total: 55 (262 Intervention: lesions) 100 (243 Comparator: lesions) of recruiting No. centres then in 1st year, a year Patients twice yearly. more tending to develop seen more lesions were FU Minimum frequently. period was 1 FU period was 5 Follow-up period and Follow-up frequency 228 Authors de Haas (2006) 229

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT is a Limited reporting of methods and results makes makes results and methods of reporting No difficult. meaningful interpretation reported on who assessed details were and whether cosmetic outcomes, blinded. outcome assessors were for reported Outcomes not always group by down or broken both groups, Authors’ conclusions to existing therapies, alternative good an excellent where particularly in areas cosmetic outcome is crucial Brief study appraisal Interpretation

mth, histological mth, There were no treatment- were There 0.001) < At 6 Morbidity no signs of were there evaluation PDT malignancy in 73% of the active group PDT placebo the in 21% vs group ( p to normal activity QoL and return Cosmetic outcome rated as excellent PDT in 95% of the active or good patients AEs AEs. serious or systemic related and erythema pain, stinging, Burning, and graded as mild or transient, were moderate Results d. d. mth were re- mth were PDT (methyl PDT (methyl hr of red light (570– hr of red . Treatment repeated after 7 repeated Treatment . 2 mg/g of methyl aminolevulinate aminolevulinate mg/g of methyl nm) with a total light dose of J/cm Lesions with PR at 3 Further PDT parameters were treated. not reported PDT group, active As for Comparator but using placebo cream Treatment details Treatment Trial treatments treatments Trial vs PDT (placebo aminolevulinate) cream) Intervention Lesions 1st prepared PDT with debridement/debulking. by 160 and 3 cream 670 75 Not Not Population details Population Treatment Treatment intention patients Curative with histologically confirmed nBCC of cancer Type(s) and histology nBCC Main eligibility criteria Patients with histologically confirmed nBCC Patient characteristics stated Concomitant treatment stated 77 mth RCT (between- Not clear, but Not clear, Study details Abstract Data source Australia Country English Language Study design participant comparison) of participants No. 66 Total: 33 Intervention: 33 Comparator: centres of recruiting No. Not stated period and Follow-up frequency to be at least 6 appeared nBCC, nodular basal cell carcinoma. nBCC, 228 (2003) et al. Authors Foley 229

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 The study This pilot Interpretation study blinded both patients and there However, outcome assessors. calculation was no mention of a power a and the sample size was very small; been more have larger study would particularly on differences informative, in pain scores Authors’ conclusions in short-term no difference found ALA–PDT and efficacy between so both can be equally MAL–PDT, as photosensitisers recommended Brief study appraisal 4.8 = 0.4), nor 0.4), = 0.92] = 4.4 for ALA vs 2.8 for ALA vs 2.8 for 4.4 for = VAS 2nd treatment: 0.09, Not assessed = Average intensity of pain did not Average Results There was no statistically was no statistically There Morbidity in incomplete significant difference ALA vs clearance rates [6/22 (27%) p 6/21 (29%) MAL, to normal QoL and return activity AEs (1st groups between significantly differ VAS treatment: p MAL, for ALA vs 3.9 for MAL, p MAL, ALA vs 3.9 for for Most pain was did character of pain. described as being burning or stinging hr mm d (but nm (from metal nm (from PDT with d giving a total dose of 2 . After illumination the area After illumination the area . 2 mW/cm J/cm Treatment details Treatment treatments Trial (ALA–PDT) vs PDT 5-aminolevulinate (MAL– aminolevulinate with methyl PDT) All tumour ALA–PDT: Intervention was removed skin level tissue above chloride spray (with ethyl curettage by plus The visible tumour, anaesthetic). in a layer was covered 5-mm margin, 2 (around ALA cream of 20% and opaque thick) and polyurethane After 3 applied. were dressings was cleaned and illuminated the area with light of 600–730 with an intensity of halogen source) 100 was covered with a light protective with a light protective was covered 1 for dressing after 7 repeated Procedure without debulking) Comparator MAL–PDT: PDT with Same methods as for except 16% group, 5-aminolevulinate was cream aminolevulinate methyl ALA used instead of 20% 75 Curative yr mm. Pigmented mm. yr mm in diameter Population details Population intention Treatment of cancer and Type(s) histology Nodular primary BCC Main eligibility criteria Patients with nodular primary on skin BCC located anywhere and hairyexcept periocular area with a clinical diameter scalp, smaller than 20 BCCs and patients with more excluded, were BCCs than five patients with porphyria, as were or contraindications to surgery, or to to daylight hypersensitivity either of the creams characteristics Patient 62 % Male: 39–87 Age range: 68 Mean age: less than Most tumours were 10 Concomitant treatment pain emollient for Topical wk 8 RCT One 84 et Authors Kuijpers (2006) al. Study details Full Data source published paper The Country Netherlands English Language Study design (between-participant comparison) of participants No. 43 BCCs in 39 Total: patients 22 BCCs Intervention: 21 Comparator: BCCs of recruiting No. centres 230 period Follow-up and frequency 231

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 A No clinically relevant comparator relevant clinically there was used, treatment on was a lack of information issues such as blinding and and the allocation concealment, many authors did not present and population details results It is therefore diagnosis. by reliable any difficult to make conclusions about the efficacy of verteporfin in patients with BCC Authors’ conclusions single course of verteporfin benefit treatment PDT showed non- patients with multiple for melanoma skin cancers Brief study appraisal Interpretation , and 100% at , 2 J/cm mth, the mth, ; superficial BCC: 63%, 80%, 80%, 63%, superficial BCC: ; Reported light dose by 2 , 82% at 120 , 2 Reported by light dose, rather Reported light dose, by 0.06) J/cm J/cm = and 97%; BCC not specified: 0%, 56% 0%, BCC not specified: and 97%; and 75% indicating a better was a trend There with a higher light dose response ( p to normal QoL and return activity rather than tumour type AEs tumour type than by At 6 Morbidity no (i.e. histopathological response 76% at nBCC: tumour) was: residual 60 Results 180

2 : : 2 2 vs 2 J/cm : See : 2 J/cm : 10 : mg/m J/cm 2 J/cm J/cm hr later of red light of red 2 ) 2 PDT at 60 J/cm . Tumours re-treated re-treated Tumours . vs PDT at 180 2 2 mm around the mm around mg/m J/cm nm) from a non-thermal nm) from mW/cm 10 40 ± mth if necessary (with dose ± min intravenous infusion of 14 min intravenous (688 LED panel. The exposed area included The exposed area LED panel. a margin of 3–4 was delivered The irradiance lesion. 200 at 3 to 18 increased See above Intervention PDT at 60 Treatment details Treatment treatments Trial Comparator PDT at 120 PDT at 120 verteporfin, followed 1–3 followed verteporfin, to 60 exposure by above 2nd comparator PDT at 180 Oral Not Curative yr yr eight = Population details Population intention Treatment of cancer and Type(s) 277 histology Superficial BCC, 93 lesions nBCC, lesions (66%); 34 lesions disease, Bowen’s (22%); BCC unspecified 17 lesions (8%); (4%) Main eligibility criteria biopsy- Patients with at least two superficial or nBCC proven lesions Bowen’s characteristics Patient (study also BCC only stated for included SCC) but overall: per tumours treated Average patient 22–79 Age range: 55 Mean age: Most patients had Fitzpatrick skin type II or III Concomitant treatment analgesic drugs for pain analgesic drugs for 68 wk, and 3, and 3, wk, mth (optional RCT (between- FU at 6 mth) et al. (2004) Authors Lui et al. participant comparison) of participants No. diagnosis Not stated by Total: (387 lesions classified as BCC) Superficial BCC Intervention: nBCC 47 lesions; 120 lesions; BCC (not specified) zero Superficial BCC Comparator: nBCC 30 lesions; 77 lesions; BCC (not specified) nine Superficial 2nd Comparator: nBCC 16 BCC 80 lesions; BCC (not specified) lesions, eight centres of recruiting No. Four period and Follow-up frequency Study details Full published Data source paper USA Countries Canada, English Language Study design 230 18 and 24 12, 6, 6 beyond 231

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Treatment Treatment This was Interpretation Authors’ conclusions more of nBCC with SE is significantly ALA– with than treatment effective PDT should PDT after debulking. be used as a standard not therefore nBCC for treatment Brief study appraisal and generally a well-conducted which draws study, well-reported conclusions and can be appropriate As the to be reliable. considered authors suggest further studies are possible variations to explore required in PDT treatment Not yr was 0.001) 0.27 < = p No serious Results 3 mth: Morbidity 3 mth: 78/83 (94%) CR in PDT and 86/88 (98%) in SE p patients, Cumulative rates: Failure incidence of failure at 3 probability SE and 30.3% 2.3% for PDT ( for QoL and return to QoL and return normal activity assessed AEs complications were observed min. This min. . Area Area . min with 2 J/cm wk prior to PDT Any incomplete Any

. 2 J/cm and dose of 75 2 ALA–PDT vs Surgical excision mWcm hr. Lesion then illuminated using a hr. was then covered and re-illuminated after 60 and re-illuminated was then covered on the same day a fractionated treatment produced with a total light dose of 150 Treatment details Treatment treatments Trial Partial tumour debulking ALA–PDT: Intervention under local anaesthetic 3 performed to lesion including applied ALA cream 20% treatment. with occlusive and covered area 5-mm surrounding 4 for dressing 15 for metal-halogen light source broadband intensity of 100 responses or recurrent tumours were re-treated re-treated tumours were or recurrent responses surgically Local anaesthetic using Comparator Surgical Excision: excision of by followed lidocaine (1%) with adrenaline Closure margin. the tumour and a 3-mm surrounding or transposition/transplantation sutures was by Sections of the lateral depending on lesion location. if examined; histologically and deep margins were as then this was regarded tumour was found residual performed were and re-excisions failure a treatment tumour from free until margins were mm mm in yr or older. yr or older. yr and use yr Population details Population Treatment intention Treatment Curative of cancer and Type(s) histology nBCC Main eligibility criteria primary untreated Previously nBCC with maximum diameter of 20 patients of 18 expectancy life Pregnancy, of less than 5 drugs of photosensitive exclusion criteria. were excluded were Tumours pigmented or if recurrent, located on hairy or concave Further details were areas. reported characteristics Patient 50 % Male: 65 Mean age: located Most tumours were back on the forehead/temple, mean Maximum or nose area. tumour diameter 9.1 Concomitant treatment Not stated yr RCT One 86 wk for surgery, surgery, wk for et Authors Mosterd (2008) al. Study details Full Data source published paper The Country Netherlands English Language Study design (between-participant comparison) of participants No. 149 (173 lesions Total: 171 randomised, treated) 85 lesions Intervention: lesions 88 Comparator: of recruiting No. centres Follow-up period Follow-up and frequency 1–2 232 12 and 18 6, then 3, 4 and 5 3, 2, mth; 233

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Interpretation Authors’ conclusions Long-term FU indicates superior efficacy of However, surgery to PDT. PDT is also an effective and exhibits a treatment cosmetic favourable more outcome Brief study appraisal well- This generally which conducted trial, was had a long FU period, papers reported in two The abstracts. and four to be likely are results although the reliable, did vary3-mth CR results reports between slightly yr, yr, mth, mth, 0.001). At 2 0.001). yr: CR was yr: < yr: 32/53 (60%) PDT yr: 0.09). Only one lesion Only 0.09). 0.04 0.15). Recurrence was Recurrence 0.15). = = = Cosmetic outcome was mth, PDT patients reported PDT patients reported mth, yr: 44/53 PDT lesions (83%) yr: mth, excellent or good in 83% excellent or good mth, mth. No significant difference at 3 No significant difference mth. 0.03. At 24 0.03. = yr, excellent or good in 33 of 42 (79%) excellent or good yr, 4.8%, ns. At 1 ns. 4.8%, = 0.001). At 36 0.001). < mth: 48 lesions (91%, 50 patients) in the PDT 48 lesions (91%, mth: 0.01). There was recurrence in 14% of lesions was recurrence There 0.01). = 0.001). At 1 0.001). Four patients in each group died during FU (all patients in each group Four < More PDT patients reported AEs [27/52 (52%) vs 14/49(29%), AEs [27/52 (52%) vs 14/49(29%), PDT patients reported More 0.007). Patients also rated global cosmetic outcome on a 0.007). 0.03]. Most AEs were transient local reactions such as burning transient local reactions AEs were Most 0.03]. mth: CR 79% in PDT group vs 96% in surgery group. Recurrence Recurrence surgeryin 96% vs group. group PDT in 79% CR mth: = = Mortality to treatment) to be unrelated considered At 3 Morbidity 47 patients) in the surgery group, and 51 lesions (98%, group, mean diff CR, showed Results had CR vs 50/52 (96%) surgery lesions ( p 4% in PDT group vs 0% in surgery group. At 2 vs 0% in surgery4% in PDT group group. 11 By this stage, lesions had CR vs 44/52 (85%) surgery lesions. lost to FU vs six (11%) surgery lesions. (21%) of PDT lesions were At vs 2% in surgery was 9% in PDT group group. Recurrence 36 At 5 vs 2% in surgerywas 10% in PDT group group. and 96% in the surgery (per-protocol 76% in the PDT group group p population, and 4% in the surgery ( p PDT group group (in the surgery group) recurred within the 3- to 5-yr FU period. within the 3- to 5-yr FU period. (in the surgery recurred group) rate that the recurrence was no evidence there In the PDT group, was higher in larger lesions to normal activity QoL and return in excellent or good At 3mth, as being: investigator rated by PDT vs 15/45 patients (33%) having 36/44 patients (82%) having surgery ( p PDT patients vs 17 of 45 (38%) surgery patients ( p excellent or good in 24/29 (83%) PDT patients vs 16 of 39 (41%) excellent or good surgery patients ( p excellent or good At 5yr, of PDT patients vs 37% surgery patients. in 27 of 31 (87%) PDT patients vs 19 35 (54%) surgery patients, p 12 and 24 4-point scale at 3, at 12 mth excellent or good in 41/42 (98%) for PDT patients vs in 41/42 (98%) for at 12 mth excellent or good p surgery, 36/43 (84%) for 28/29 (97%) vs 27/36 (75%) for surgery, p surgery, 28/29 (97%) vs 27/36 (75%) for AEs p One PDT patient had to or erythema. skin pain, sensations, surgery three burning sensation; due to a severe stop treatment patients had skin infections from from 2 mm MAL– ), mean light ), 2 mW/cm hr. Cream Cream hr. nm, total fluence nm, , fluence rate of 50 , 2 mW/cm mg/g), each comprising mg/g), J/cm mm thick and to 5 a standard light source a standard 2nd 3mth, If not CR by cycle administered. treatment with 76% of lesions treated one cycle only Comparator Simple elliptical excision surgery with at least 5-mm margins. Local anaesthesia to 200 Treatment details Treatment treatments Trial PDT vs excision surgery Intervention Surface scale using scalpel or removed anaesthesia). (without curette PDT cycles Then one or two aminolevulinate with methyl (160 sessions (1 wk of two was applied Cream apart). 1 then tissue, of surrounding with an occlusive covered 3 for dressing then washed off with 0.9% saline solution immediately illumination with before light red non-coherent (570–670 75 density of 127 yr yr (PDT yr (surgery mm in diameter. mm in diameter. yr. Patients with more Patients with more yr. 18 Population details Population intention Treatment Curative of cancer and Type(s) histology Primary nBCC Main eligibility criteria confirmed Histologically previously nBCC, in patients untreated ≥ porphyria, than 10 lesions, or Gorlin syndrome Further excluded. were exclusion criteria were reported characteristics Patient 60 % Male: 38–95 Age range: 69 Mean age: 67 group), group) 90% of patients Around and one lesion, had only of three-quarters around 5 between lesions were and 14 The majority of patients classified as were Fitzpatrick skin type II or mostly and lesions were III, on the face/scalp/trunk and neck mth, mth, et al. et al. 3 RCT 192–197 13 85 yr Authors Rhodes (2007) Follow-up period Follow-up and frequency (between-participant comparison) of participants No. 103 randomised Total: (101 treated) 53 (60 Intervention: lesions) 50 (58 Comparator: lesions) of recruiting No. centres Study details Linked publications Full Data source published paper stated Not Countries hospitals’ ‘European English Language Study design 232 4 and 3, 2, then at 1, 5 233

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 The therapeutic The therapeutic This was a pilot study in preparation for a larger clinical for study in preparation been to have it is likely As such, trial. to detect statistically underpowered for at least some significant differences Treatment of the outcomes investigated. described but well methods were such as methods of study methods, concealment of allocation randomisation, in detail not reported were and blinding, Authors’ conclusions outcome of this pilot study showed ALA PDT with between no difference will This preliminary result and mALA. research confirmation in further require Brief study appraisal Interpretation

After a second

wk after the 1st During illumination, eight ALA eight During illumination, ALA group: 44 of 72 BCC ALA group: Morbidity a CR 12 (61%) showed 23 of 40 BCC vs mALA group: treatment (58%) NS significant was no statistically There in partial successes (reduction difference of the diameter BCC at least 50% of the initial tumour size) between tumours (4%) in the Three the groups. and one BCC (3%) did not ALA group no and showed to treatment respond These patients in tumour size. reduction Eight surgical treatment. given were in the and five ALA group BCCs in the a recurrence developed mALA group during the 6-mth period. and ALA group lesions in the seven PDT, treated were in the mALA group seven successfully to normal activity QoL and return Not assessed AEs mALA patients patients and five painful experienced moderately (1–4 on the are sensations in the treated patients in the mALA Two pain scale). had stabbing pain sensations group 6–7 on the pain scale) during (level and had to be treated laser application patients in Five with local anaesthetic. felt in mALA group and two ALA group moderate pain sensations up to the 3rd post illumination (1–3 on the pain day scale) Results mm beyond mm beyond mm was mm. The procedure The procedure mm. ALA-based PDT vs mm thick. The area was The area mm thick. and the energy density was 2 . A diameter of the irradiated A diameter of the irradiated . 2 hr later, residues were removed removed were residues hr later, J/cm W/cm 120 selected and distance laser-diffuser-skin selected and distance laser-diffuser-skin to 15 corresponded with or without local was performed to the pain anaesthesia according In management needs of the patient. partially was only treatment cases where was repeated the therapy successful, after the final examination (12th wk). not Further PDT parameters were reported ‘Intervention’ for Comparator See details area of approximately 10 of approximately area Treatment details Treatment Trial treatments treatments Trial mALA-based PDT ALA and mALA gels Intervention less than 1hr before prepared were dissolving in a cold (approx by treatment F-127) up to a 4°C) thermo gel (Lutrol ALA (mALA)/ml concentration of 10% 3 The gel was applied (w/v). the visible margin of tumour and was 5 approximately from with plaster and protected covered 3 light. with a blue skin circled and tumour areas The lesion was then illuminated marker. with a diode laser equipped density was The power fibre. microlens 0.1 mm yr yr Not stated mm). Three Three mm). mm), no morpheic mm), 2 Population details Population (range 3–12 patients with GGS were included in the study Concomitant treatment Treatment intention Treatment Curative of cancer and Type(s) histology Superficial BCC Main eligibility criteria Histologically BCC of the skin, verified proven histologically superficial BCC with no deep infiltration (< and pigmented BCC patient compliance. good Exclusion criteria were: Unclear histology, expected nBCC, clinically poor compliance of untreated the patient, diabetes mellitus and pregnancy Patient characteristics 54 % Male: 42–96 Age range: Mean age 74 The vast majority of the located in tumours were the head and neck area. diameter The average of the lesions was 7 2, 4 2, mth RCT One wk and 6 81 Study details Full Data source published paper Country Germany English Language Study design (between-participant comparison) of participants No. 24 (112 lesions) Total: 13 Intervention: 11 Comparator: of recruiting No. centres Follow-up period Follow-up and frequency and 12 GGS, Gorlin–Goltz syndrome. GGS, after primary treatment 234 Authors Schleier et al. (2007) 235

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 nm, but nm, Topical ALA– Topical Although this nm was used for the laser group, for for the laser group, nm was used for Interpretation Authors’ conclusions halogen light PDT with a broadband rates and cosmetic cure gives source outcome similar to those obtained with a laser source Brief study appraisal there study, was quite a well-conducted still issues which question the were the authors of its results: reliability that the optimum acknowledged ALA–PDT is 635 for wavelength 630 light doses varied of practicality; reasons patients within a treatment between and the M/F ratio differed group; the treatment between substantially groups

During the 1st wk after treatment During the 1st wk after treatment 0.075). Results were scored as being scored Results were 0.075). 0.49) in response rates (complete, rates (complete, 0.49) in response = = Results Overall there were no statistically no statistically were there Overall results in cosmetic significant differences ( p in 80 lesions (84%) excellent or good vs 102 lesions (92%) in the laser group the lamp group AEs and 74% of the 68% of the laser group some patients reported lamp group stinging, of discomfort (e.g. degree no statistically were There pain). itching, the between significant differences AEs either during or after for groups reported No SAEs were treatment. during 6-mth FU period Overall, there were no were there Morbidity Overall, significant differences statistically ( p the groups or none) between partial, laser [CR was 95/111 lesions (86%) for Patients lamp]. vs 110/134 (82%) for up beyond followed with CR were Data were 6-mth period. the protocol analysed but not statistically presented, in after 2 yrs occurred – recurrence and five the laser group, lesions for four the lamp group lesions for to normal activity QoL and return

2 ) 2 J/cm mW/cm min followed min followed 2 PDT-laser vs PDT- PDT-laser , and a light dose of , mW/cm 2 (median dose 100 2 with median light dose of including infra- irradiance Total . J/cm mW/cm 2 2 nm from a copper vapour laser a copper vapour nm from J/cm J/cm Treatment details Treatment and total light dose ranged from 150– and total light dose ranged from 200 PDT-broadband lamp: As lamp: Comparator PDT-broadband was except light source PDT-laser for lamp, a 150W halogen bulb broadband 570 and light of between giving filtered was 100–180 Irradiance 740nm. 200 was 135–240 red 100–150 Trial treatments treatments Trial lamp broadband Pre-treatment Intervention PDT-laser: with 99% soaked with dressing 15 for dimethylsulphoxide with and covering ALA cream 20% by was Cream 3h. for dressing occlusive to light exposure washed off before of 630 of Irradiance laser. pumping a dye 120–150 mm, and mm, yr cm. Patients with cm. 1 3 Population details Population Treatment intention Treatment Curative of cancer and Type(s) histology Superficial BCC Main eligibility criteria Patients with histologically/ confirmed cytologically superficial BCC with thickness < diameter < than six lesions fewer characteristics Patient 47 % Male: 62 Mean age: All Caucasian Concomitant treatment Not stated One wk, and 3 wk, 82 mth. Some mth. yr et al. Authors Soler et al. (2000) Study details Full Data source published paper Country Norway English Language Study design RCT (between- participant comparison) of No. participants 83 (245 Total: lesions) 41 Intervention: (111 lesions) 42 Comparator: (134 lesions) of recruiting No. centres period Follow-up and frequency FU at 1 234 and 6 participants also up after 1 followed and 2 235

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 MAL–PDT This was a well- reported and conducted trial; however, however, reported and conducted trial; useful provide FU would longer-term It rates. outcome data on the recurrence was not clear if the study adequately equivalence of to show powered that included patients Given treatments. to those eligible for restricted were highlighted it as the authors have surgery, be more seems plausible that PDT may here than shown effective Authors’ conclusions of efficacy and excellent has high levels cosmetic outcomes when treating as an sBCC and should be considered to surgeryalternative Brief study appraisal Interpretation

Treatment-related AE were higher AE were Treatment-related 0.001 < (all per protocol analyses) Morbidity (all per protocol 118/128 3-mth complete lesion response: PDT vs 117/118 (99%) in (92%) for surgery 11/118 (9%) 12-mth lesion recurrence: surgery PDT vs 0.117 (0%) for for to normal activity QoL and return patient Cosmetic outcome assessed by in both cases PDT and investigator, was judged to be superior treatment rated assessment: 12-mth investigator for (51%) 44/86 and PDT for (93%) 77/83 ‘success’, as a considered surgery were p AEs in the PDT (37%) than surgery (15%) of mild AEs were Most related group. most and were to moderate severity photosensitivity (31%) commonly infection PDT and wound for reaction surgery(5%) for patients 11% of PDT patients with related while 57% of treatment AEs required AEs needed surgery patients with related treatment that were recorded No SAEs were to either to be related considered treatment Results . . 2 d J/cm hr. Cream Cream hr. MAL–PDT vs Surgery mm of skin and covered mm of skin and covered mg/g of MAL cream was mg/g of MAL cream mm thick to the lesion and min, total light dose 37 min, Mini-desk fans were provided to cool the provided Mini-desk fans were sites during light exposure irradiation One simple Comparator Surgery: elliptical excision surgery was performed routine to the investigators according practice with an estimated 3-mm margin estimated edge of the lesion from Treatment details Treatment treatments Trial Patients Intervention MAL–PDT: 7 sessions, treatment two received prior to prepared Lesions were apart. each session if deemed necessary by the crusts and roughening removing 160 surface. 1 applied 5–10 surround 3 for dressing with an occlusive was washed off using saline solution light from exposed to red and the area for between a large-field LED source 7 and 10 yr yr with yr mm or larger than mm were excluded mm were Population details Population Treatment intention Treatment Curative of cancer and Type(s) histology Superficial BCC Main eligibility criteria 18 Patients over confirmed histologically primary sBCC suitable for simple excision surgery. than five Patients with more lesions in the mid- lesions, lesions smaller face area, than 8 20 (other criteria reported) characteristics Patient 67 % Male: 31–92 Age range: 64 Mean age: Caucasian, All patients were of lesions and the mean no. per patient was 1.4 (range Most lesions were 1–5). located on the trunk or neck Concomitant treatment on treatment concurrent was not the lesion areas permitted 3, 6 3, 80 27: 10 in 27: mth Authors Szeimies (2008) et al. Study details Full Data source published paper Countries Germany, Australia, UK Switzerland, English Language Study design RCT (between- participant comparison) of No. participants 196 (182 Total: analysed) 100 Intervention: 96 Comparator: of recruiting No. centres 236 10 in Germany, UK, in Switzerland, two Australia in five period Follow-up and frequency and 12 237

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT was Very little Very Authors’ conclusions superior to and histologically clinically nBCC placebo PDT in treating Brief study appraisal in this was available information clear It was not always abstract. lesions or for were whether results individual patients Interpretation

d in All SAEs in both

There were no systemic AEs in no systemic were There d in active PDT group vs 3–6 PDT group d in active 0.001 < Complete clinical response Morbidity Complete clinical response PDT active was 80% (33/41 lesions) for placebo vs 51% (20/39 lesions) for Complete histological response PDT. was 78% (32/41 lesions) vs 33% (13/39 to be at both appeared lesions), p to normal activity QoL and return complete clinical sites showing For cosmetic investigator-assessed response, in 93% outcome was excellent or good PDT vs 90% of placebo of active Patient satisfaction with PDT compared was better in treatment with previous and 52% in 60% of MAL–PDT patients, placebo PDT patients AEs 91% in the AEs: Local either group. vs 75% in the placebo group active Mild to moderate erythema, group. in both and pain found stinging, burning, a median for Pain occurred groups. of 2 placebo PDT group. to treatment not related were groups Results mth were mth were wk apart) of MAL–PDT (methyl MAL–PDT (methyl Trial treatments treatments Trial vs PDT (placebo aminolevulinate) cream) Patients Intervention MAL–PDT: cycles (1 two received was There PDT. aminolevulinate methyl surface debridement and slight lesion BCC with debulking prior to PDT. partial at 3 clinical response Further PDT parameters re-treated. not reported were MAL–PDT using As for Comparator placebo cream Treatment details Treatment

Not stated Treatment intention Treatment Curative of cancer and Type(s) histology nBCC Main eligibility criteria Not stated characteristics Patient Not stated Concomitant treatment Population details Population RCT Not clear, Not clear, Not stated mth 78 but appeared to be at but appeared least 6 but described as being multicentre period and Follow-up frequency Study details Abstract Data source Country USA English Language Study design (between-participant comparison) of participants No. 65 (80 lesions) Total: 33 patients Intervention: (41 lesions) 32 patients Comparator: (39 lesions) of recruiting No. centres 236 et al. Tope Authors (2004) 237

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 15 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 ALA–PDT This study was generally quite well conducted and the quite well generally However, to be reliable. likely are results on losses to FU and information more would sample size calculation used, any been useful have Authors’ conclusions is comparable with cryosurgery BCCs. modality for as a treatment common with more are Retreatments be performed but this can easily PDT, less due to shorter healing times, and better cosmetic outcome, scarring, ALA–PDT which follows Brief study appraisal Interpretation

yr 0.05) < p mth, favouring favouring mth, 0.001), but not 0.001), 0.05) < < p 0.001), and 0.001), < yr in the PDT group for for yr in the PDT group One patient died in each There was no statistically was no statistically There wk, the PDT group had a significantly had a significantly the PDT group wk, Mortality Both deaths after the 3-mth FU. group treatment its and BCC to unrelated were participants in the PDT Morbidity More 30%) (13/44, had to be re-treated group with the cryosurgery compared group rate at 1 The recurrence 3%). (1/39, 25% (11/44, was higher in the PDT group though not statistically 15%), vs 6/39, fewer had significant (and the PDT group After obvious recurrences). clinically 1 shorter healing time in terms of leakage and oedema ( was also a significant There erythema. in leakage at 1 difference The cosmetic outcome was significantly better at 1 scar formation, hypopigmentation, (all p tissue defects the PDT group to normal activity QoL and return ( p hyperpigmentation AEs in mean pain significant difference (PDT during treatment scores VAS One PDT 43 vs cryosurgery 32). One local anaesthetic. patient required cryosurgery a bacterial patient developed During site. at the treatment infection eight PDT post treatment the 1st week cryosurgerypatients and two patients used analgesic medication ( Results , , 2 . . 2 J/cm mW/cm min in between. min in between. s each time, with s each time, C. Additional Additional ° C. ALA–PDT vs wk examinations hr after ALA, 635-nm light through a 635-nm light through ALA, hr after Larger lesions had to be illuminated with Patients than one light source. more received with pain during light exposure at 15–20 water spray was evidence if there given treatment 8 or at the 4, tumour growth of residual 12 with a liquid Treatment Comparator Two technique. spray a using unit nitrogen and the given, cycles were freeze–thaw 25–30 for frozen area period of 2–4 a thawing was if there given treatment Additional at tumour growth of residual evidence 8- or 12-wk examinations the 4-, and the mean fluence rate 80 Treatment details Treatment treatments Trial Cryotherapy 1st Intervention Lesions were of stratum corneum (removal prepared material using scalpel/96% alcohol/ ALA was then 20% isotonic saline). and to lesion with 1-cm margin, applied dressing. with a thin occlusive covered 6 (with a clear-cut 600- µ m optical fibre laser was a Nd:YAG polished end) from The single light dose was 60 applied. yr Population details Population Treatment intention Treatment Curative of cancer and Type(s) histology Non-morphoeic BCCs (superficial and nodular) Main eligibility criteria with Patients aged 20–90, verified histopathologically both BCCs suitable for were PDT and cryosurgery, Exclusion criteria eligible. also were pregnancy) (e.g. reported characteristics Patient 50 % Male: 42–88 Age range: 39 patients were There with superficial BCCs and 54% were 49 with nBCCs. 28% on head on the trunk, and 11% on legs, and neck, 7% on arms treatment Concomitant Local anaesthetic available Use during procedures. of analgesic drugs was pain relief permitted for following during the week procedures FU wk, wk, RCT One yr 88 et al. et al. Wang Authors (2001) Study details Full Data source published paper Country Sweden English Language Study design (between-participant comparison) of participants No. 88 Total: 47 Intervention: 41 Comparator: of recruiting No. centres Follow-up period Follow-up and frequency 8 and 12 4, at 1, 238 and at 1 239

Appendix 16 Barrett’s oesophagus data extraction

238 239

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 ALA–PDT can This small study Interpretation was generally well conducted, and the conducted, well was generally it should However, reliable. appear results to have appear be noted that no results AEs in the placebo been reported on and it was unclear to which FU group, relate the main study results Authors’ conclusions low- of ablation effective and safe provide grade dysplastic epithelium Brief study appraisal 0.001). 0.001). mth < hr). No patients hr). 0.001). All regression All regression 0.001). < Not assessed p Not assessed All PDT patients experienced chest d, and was aggravated by swallowing swallowing by and was aggravated d, Results Mortality 16/18 Morbidity In the PDT group of evidence macroscopic (89%) showed compared at FU endoscopy, regression with 2/18 (11%) in the placebo group; median reduction the corresponding PDT vs 0% for 30% for were in areas placebo (both cases displayed normal squamous mucosa normal squamous mucosa cases displayed in was a reduction There when biopsied. of the of dysplasia in favour prevalence p (0/18 vs 12/18, PDT group No results complained of dysphagia. the been reported for to have appeared placebo group use Resource Although it was unclear as to which FU the authors to, relate point these results of treatment did state that the effects up to 24 maintained for were AEs that persisted for pain during treatment 3–5 a One patient developed or coughing. to sunlight mild skin rash on exposure within 48 (resolved ) so 2 mg/ J/cm ml of orange s per 3-cm length. s per 3-cm length. ALA–PDT vs hr hr later by laser hr later by for 500 for 2 s, energy density 60 s, nm) at a power density of nm) at a power cm of Barrett’s mucosa). This mucosa). cm of Barrett’s cm of oesophagus was treated cm of oesophagus was treated mW/cm Treatment details Treatment 4 juice) followed sedation (under intravenous endoscopy and analgesia) when the extent of A copper was recorded. area Barrett’s with a fibre by laser delivered vapour green a diffuser tip was used to deliver light (514 120 Trial treatments treatments Trial Placebo-PDT Intervention Patients drank 30 in 50 ALA (dissolved kg that 6 (upper 6 of complete treatment represented epithelium in one-half of the Barrett’s in hospital Patients remained patients. advised to avoid and were until dark, 24 bright light for except above, As for Comparator orange juice alone was used as placebo All patients had two separate treatments separate treatments All patients had two total treatment then proximal, (distal, time 1000 cm yr yr mg omeprazole daily cm in length, who were who were cm in length, Population details Population Treatment intention Treatment Curative of cancer and Type(s) histology BO – LGD Main eligibility criteria Patients with LGD in least at of BO circumferential 3 omeprazole were receiving histological However, eligible. after biopsy re-examination had to confirm the diagnosis characteristics Patient 83 % Male: 30–71 Age range: 56 Median age: Range of pre-treatment 3–15 lengths of Barrett’s: Concomitant treatment analgesic given Patients were and antiemetic drugs as treatment. following required also supplied Patients were as with antacids to take the Throughout needed. and FU period treatment maintained on patients were 20 95 Not mth Ackroyd Authors (2000) et al. Study details Full Data source published paper Country UK English Language Study design RCT of No. participants 36 Total: 18 Intervention: 18 Comparator: of recruiting No. centres stated period Follow-up and frequency 12 and 6, FU at 1, 24 240 oesophagus. Barrett’s BO, 241

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 ALA–PDT The absence of mg/kg should provide optimal mg/kg should provide important methodological, population, population, important methodological, details in this abstract of and result means it is difficult to a small study, of its results assess the reliability Authors’ conclusions at 30 conditions in BO treatment Brief study appraisal Interpretation Not assessed Not assessed In the 30-mg/kg group, one patient In the 30-mg/kg group, Mortality Morbidity Not assessed AEs but no other had mild photosensitivity, In the 50-mg/kg group, seen. AEs were and hair loss, oesophageal discomfort, function transient disturbance of liver observed were test results use Resource Results hr mg/kg ALA–PDT 30 mg/kg vs placebo mg/kg, or placebo, was followed 4 was followed or placebo, mg/kg, later by light administration. No further light administration. later by reported parameters were ‘Intervention’ Comparator See ‘Intervention’ 2nd comparator See Treatment details Treatment treatments Trial ALA–PDT 50 vs ALA at 30 or Intervention Oral 50 Not Not Curative Curative Population details Population Treatment intention (dosing study) of cancer Type(s) and histology Dysplastic BO Main eligibility criteria Not stated Patient characteristics stated Concomitant treatment stated RCT Not stated 96 et al. et al. Ackroyd Authors (1996) Study details Abstract Data source Country UK English Language Study design 240 of participants No. 28 Total: Not stated Intervention: Not stated Comparator: centres of recruiting No. Not stated period and Follow-up frequency 241

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 APC alone This was a Interpretation small trial and the low numbers of numbers small trial and the low may groups the three patients across was insufficient meant there have differences to detect treatment power A further problem existed. they where is that all patients who did not APC, given were adequately respond of PDT alone so the long-term effect is unclear Authors’ conclusions ALA–PDT in combination with or of APC can lead to complete reversal epithelium in at least two- Barrett’s of patients when administered thirds The sessions. treatment in multiple use of authors did not recommend prophylactic these techniques for ablation of BO Brief study appraisal 0.05) < wk, mean endoscopic wk, Not assessed 0.01). There were were There 0.01). < Not assessed 23 of 26 patients across the 23 of 26 patients across 0.01). Differences in odynophagia, in odynophagia, Differences 0.01). < Results Mortality At 6 Morbidity was 51% (range BO surface reduction 20–100%) in the single dose PDT 86% (range 0–100%) in the group, and 93% fractionated PDT group APC group. (range 40–100%) in the for significant This was statistically single-dose the comparison between PDT and fractionated dose Differences APC. single-dose PDT and fractionated dose PDT and between Rates of not significant. APC were ns between complete ablation were 12- and 18-mth data 6-, the groups. then not extracted as patients were APC eligible to receive AEs of 14 in the and five PDT groups two experienced pain during APC group ( p treatment cases of nausea and vomiting more p APC, with PDT (7 vs 0 in and patients had more elevated liver liver elevated and patients had more in tests (20 vs 0, enzyme results p death and stricture sudden fever, not significant were formation use Resource ml hr. hr. cm. cm. hr hr after at 1 l/min at a 2 at 4 100) ALA vs 100) 2 APC involved a APC involved +

J/cm W. The aim was to W. PDT with J/cm hr after ALA hr after at 4 2 2 J/cm nm. PDT was performed PDT was performed nm. mW/cm mg/kg ALA was dissolved in 20 ALA was dissolved mg/kg Trial treatments treatments Trial fractionated dose (20 Treatment details Treatment APC ALA vs PDT with single-dose Intervention Fractionated PDT: 60 All patients were of orange juice. 36 for room in a darkened kept laser module was A KTP/532 dye light at a wavelength used to deliver of 630 with a fluence of 20 Single-dose ALA–PDT: ALA–PDT: Comparator Single-dose fractionated PDT with the As for was a single exception that there illumination of 100 administration. Light delivery was administration. using an inflatable balloon performed with an inflated diameter of 2.5 Calculated total fluence rate was 100 and 100 ALA administration Argon an 2nd comparator APC: APC 300 was used Beamer 2 device, rate of 2 with a gas flow setting of 65 power of the oesophageal ablate two-thirds of BO during the 1st circumference session to session and in the following ablate the remainder. sessions treatment of two maximum per patient at 4-wk intervals mth If Curative cm (range yr yr wk, the remaining the remaining wk, cm and specialised yr or over with BO yr or over mg of omeprazole for the mg of omeprazole for mg (range 40–80mg) cm) Dysplasia: None 32; LGD None 32; cm) Dysplasia: complete elimination of BO was the designated by not achieved at 6 treatment APC additional BO was ablated by sessions of two with a maximum Patients were at 4-wk intervals. dose of at with a daily treated least 40 Mean dose duration of the study. 47.5 Population details Population intention Treatment of cancer and Type(s) histology Patients with BO without dysplasia or with LGD Main eligibility criteria Patients 18 without dysplasia or with LGD on histological examination were a BO Patients had to have eligible. length of 2–5 All patients intestinal metaplasia. at least 6 taking PPIs for were Exclusion criteria treatment. before intolerance to (repeated) were acute pregnancy, endoscopy, diseases and intercurrent porphyria survivalprecluding during the study period characteristics Patient 78 % Male: 59 Median age: 41–72 Age range: 3 Mean BO length: 2–5 eight Concomitant treatment 198 wk, wk, 6 mth RCT et al. et al. Not stated 97 100: 13 100: + Authors Hage (2004) Study details publications Linked Full Data source published paper The Country Netherlands English Language Study design of participants No. 40 Total: PDT Intervention: 20 Comparator: 13 PDT100: 2nd Comparator: 14 APC: of recruiting No. centres 18 and 24 12, 6, 242 period Follow-up and frequency 243

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 mg/kg Low dose ALA– dose Low This was a small Interpretation Authors’ conclusions the for protocol to be a safe PDT appears The authors recommend ablation of BO. as 30 orally ALA should be given that activation and could be 4- to 6-hr before at home taken Brief study appraisal study that aimed to establish optimum Although patients were dosage regimes. no information randomised to treatment, on blinding or allocation concealment to The sample size appears was provided. the authors’ been too small to view have conclusions as being reliable mg/kg groups (all 60%), (all 60%), mg/kg groups mth FU all patients Not assessed Not assessed No major AEs – no perforations or AEs – no perforations No major Results Mortality At 1 Morbidity of Barrett’s in the area a reduction showed median area, epithelium in the treated all 25 patients was 60%. for reduction varied between in area Median reduction group. each treatment 30% and 60% for seen in the were reductions The greatest fractionated and 30 was not statistically but this difference significant AEs in Significant N&V occurred strictures. further anti- 32% of patients who required common N&V was more emetic treatment. the higher dose in patients who received patients had a documented Five ALA. of mild – all were photosensitivity reaction cases use Resource . . 2 mmHg J/cm hr hr hr ml of orange nm, 2W nm, hr mg/kg) at 4- or mg/kg ALA–PDT mg/kg mg/kg ALA–PDT, light ALA–PDT, mg/kg mg/kg ALA–PDT, light ALA–PDT, mg/kg ALA–PDT at various hr mg/kg ALA–PDT, light ALA–PDT, mg/kg mg/kg ALA–PDT, light ALA–PDT, mg/kg hr, light delivered by by light delivered hr, for a total dose of 85 for 2 mg/kg or 60 mW/cm delivered by endoscopy after 4-hr PDT endoscopy by delivered in 50 ALA dissolved protocol: in dimly Patients kept orally. juice and taken At appropriate prior to treatment. lit room with endoscopy time patients underwent analgesia and an sedation, intravenous was Balloon applicator antiemetic drug. in the oesophagus a guidewire placed over and position confirmed endoscopically. 20 Balloon was inflated to around a 5-cm cylindrical by and light delivered Red light (635 diffuser fibre. diode laser) was used at fluence rate of 68 6-hr incubation times or with fractionated illumination Intervention 30 Treatment details Treatment treatments Trial doses (30 Patients recovered in a dimly lit room, lit room, in a dimly Patients recovered discharged with oral analgesia and advice to 24 bright lights for avoid after 4 endoscopy by delivered 4th comparator 60 after 6 endoscopy by delivered Comparator 30 after 6 endoscopy by delivered at 2 repeated after 4 endoscopy comparator 60 3rd 2nd comparator 30 yr mg yr 40 Curative cm (range cm), no patients no cm), Type(s) of cancer Type(s) and histology Non-dysplastic BO Main eligibility criteria Patients participating already in a large cohort study on BO with biopsy proven epithelium Barrett’s Patient characteristics 80 % Male: 63 Median age: 31–81 Age range: Median length of epithelium Barrett’s was 4 2–15 had high or LGD on biopsy Concomitant treatment esomeprazole daily Population details Population Treatment intention One 102 Study details Full Data source published paper Country UK English Language Study design RCT of No. participants 25 Total: Five Intervention: Five Comparator: 2nd Comparator: Five Comparator: 3rd Five 4th Comparator: Five of recruiting No. centres period Follow-up and frequency 4 wk 242 et Authors Kelty (2004) al. 243

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT and APC are APC are PDT and This was a was of BO patients 102 relatively robust comparative trial (despite comparative robust relatively also have which would the sample size), the use of blinded outcome benefited from its like this study, However, assessors. dosing study related Authors’ conclusions APC appears ablating BO. for both effective but larger studies should effective more development assess impact on carcinoma Brief study appraisal Interpretation without dysplasia; such patients are often such patients are without dysplasia; appear so the results at all, not treated to clinical to be of limited use in relation practice 0.0001 < d. No oesophageal d. Not assessed Not assessed Major side effects for PDT were PDT were for Major side effects 0.016. The median number of treatments of treatments The median number 0.016. 0.189 = = Mortality treatments fewer Morbidity Significantly (median APC group in the performed were (median 5), 3) than in the PDT group p in successful ablation was two for required APC group, in the and three the PDT group p of the reversal Complete macroscopic columnar segment to squamous epithelium in 50% of PDT patients and was achieved p APC patients, 97% of AEs or perforations. minimal with no strictures in 32% of Significant N&V occurred further antiemetic patients who required cutaneous reported patients Five treatment. photosensitivity (mild erythema and pain). discomfortAPC patients reported All transient dysphagia and 91% reported with resolved All were and odynophagia. 3 oral analgesia over one patient occurred, perforations dysphagia to solids and required developed dilatations four use Resource Results hr. hr. W. APC W. cm distal to mg/kg of ALA mg/kg of mmHg. Light mmHg. and total light nm 3W) at a 2 ALA–PDT vs APC ALA–PDT vs mW/cm hr later). Endoscopy was Endoscopy hr later). mm wide at each pass. mm wide at each pass. . Patients were discharged Patients were . 2 ml of orange juice taken ml of orange juice taken wk – if residual Barrett’s Barrett’s wk – if residual J/cm l/min and power setting of 65 l/min and power probe passed down biopsy channel and passed down probe 1 positioned with tip of probe the end of the scope. APC performed in a APC performed the end of scope. linear fashion coagulating strips of tissue 2 approximately was circumference One-half of the affected one sitting on the rationale at any treated Repeat chances of stricture. of reducing APC as per PDT but using treatment dose of 85 Trial treatments treatments Trial 30 ALA–PDT: Intervention in 50 dissolved orally, patient kept in a dim room prior in a dim room patient kept orally, (46 to treatment sedation, out (with intravenous carried analgesia and an antiemetic) a balloon a guidewire was placed over applicator and (position confirmed endoscopically) 20 approximately inflated to Treatment details Treatment using a cylindrical diffuser was delivered red laser light (635 – fibre fluence rate of 68 and advised to avoid bright lights for 24 bright lights for and advised to avoid at 4 Follow-up epithelium patient was re-treated until epithelium patient was re-treated was complete or to a re-epithelisation treatments of five maximum as per PDT endoscopy APC: Comparator APC generator set with gas flow protocol. of 2 mg yr 40 Curative cm, range 2–15cm). range 2–15cm). cm, Type(s) of cancer Type(s) and histology BO Main eligibility criteria Patients to invited were part from take an endoscopic screening programme 150 were (over No approached). further details reported Patient characteristics 81 % Male: 28–83yr Age range: 61 Median age: All patients had biopsy proven epithelium Barrett’s (median length of 4 No patients had high or LGD Concomitant treatment esomeprazole daily, as analgesia oral with required Population details Population Treatment intention 1 RCT 199–201 One 98 wk then 6, 12 wk then 6, et al. et al. Authors Kelty (2004) Study details Linked publications Full Data source published paper Country UK English Language Study design participants of No. 72 Total: 35 Intervention: (PDT) 37 Comparator: (APC) of recruiting No. centres and 24 mth after successful treatment sessions or five 244 period Follow-up and frequency 4 day, 245

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 mg red mg red PDT with This trial, This trial, mg/kg activated mg/kg with green or red or red mg/kg with green J/cm red laser light has high J/cm red Interpretation although small, was able to suggest a although small, with 60 effectiveness greater would need to be Such findings light. AEs confirmed in larger trials and any documented Authors’ conclusions ALA at 30 eradication of for laser is ineffective ALA at 60 HGD in BO. 1000 by for HGD in BO efficacy Brief study appraisal 0.01) = mg mg ALA green ALA green mg Not assessed 0.005) = AEs were not all reported by by not all reported AEs were 0.03) and than 30 = Results Mortality Morbidity Phase 1 4 of 16 patients (25%) had HGD one green light, red eradicated (three light) interim The trial was paused following to Phase 2 It then proceeded analysis. Phase 2 Six of six patients in the 60-mg red had successful treatment, light group was successful in one of five whereas ( p light group the 60-mg green light was also more ALA red 60-mg light ALA red successful than 30-mg ( p light ( p AEs 60 All patients receiving group. self-limiting minor, PDT showed of their abnormalities in the results function tests liver use Resource Not assessed nm nm delivering nm delivering mg/kg ALA mg/kg ALA mg/kg ALA–PDT with red ALA–PDT with red Laser treatment Laser treatment mg/kg). Patients mg/kg). 2. J/cm hr after oral ALA hr after oral mth apart Trial treatments treatments Trial light ALA–PDT with green light vs Intervention Phase 1 (eight patients) at 635 light: ALA with red a dose of 200 Treatment details Treatment was applied 4 was applied administration (30 with treatments up to three received PDT 1 Phase 2 (six patients) but with 60 As above Comparator Phase 1 (eight patients) light at 512 ALA with green intervention otherwise as for Phase 2 (five patients) but with 60 As above Not All Curative mth prior to PDT. mth prior to PDT. Treatment Treatment intention of cancer Type(s) and histology BO with HGD Main eligibility criteria Patients with BO HGD. not Patients were to receive allowed or chemotherapy within radiotherapy 1 Other exclusion provided criteria were Patient characteristics stated Concomitant treatment PPIs. patients received fluids and Intravenous given antiemetics were pre-operatively Population details Population 202–204 RCT wk then every wk then every 4 mth for the 2nd year, the 2nd year, mth for 105 mth for the 1st year then the 1st year mth for et al. et al. Authors Mackenzie (2008) No. of participants No. 27 Intervention (ALA Total: 14 light): with red (ALA with green Comparator: 13 light): centres of recruiting No. One period and Follow-up frequency 3 6 every then yearly 244 Study details publications Linked Full paper Data source Country UK English Language Study design 245

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 The preliminary data suggest that This trial was reported in abstract This trial was reported Interpretation Authors’ conclusions ALA–PDT is both safer and potentially more effective than effective more and potentially ALA–PDT is both safer PDT with Photofrin but FU is short and not all patients in the as yet been treated trial have Brief study appraisal The not available. so full details of the methods are only form need confirmation in but would promising are data presented longer FU and with all the planned patients treated 0.05. 0.05. < 0.05) 0.05). There There 0.05). < < Not assessed Not assessed Strictures developed in six of 16 developed Strictures Results Mortality patients are Morbidity Five (three therapy repeat undergoing Remission rates ALA). two Photofrin, ALA–PDT 14 of (100%) in the are and nine of 14 (64%) in the group ( p Photofrin group AEs with Photofrin and patients treated ALA (probably with one of 16 treated p to treatment), not related Skin photosensitivity developed in Skin photosensitivity developed with of 16 patients treated seven one of whom had to be Photofrin, No briefly admitted to hospital. instances of photosensitisation were ALA ( p with found were no other significant differences no other significant differences were side effects regarding groups between use Resource ALA– mg/kg ALA mg/kg J/cm of red J/cm of red Treatment details Treatment treatments Trial PDT vs with Photofrin Intervention 60 1178 activated by laser light Comparator Photofrin PDT with the standard or as previously protocol to be the most shown (no further details effective given) Not Not Not Population details Population stated of cancer Type(s) and histology BO with HGD Main eligibility criteria Patients with BO by HGD confirmed independent two pathologists were the trial. eligible for of nodules visible Any removed HGD were and patients only if residual treated HGD was still present Patient characteristics stated Concomitant treatment stated Treatment Treatment intention yr RCT 104 Not stated mth and 1 wk, 4 wk, Authors Mackenzie (2008) et al. Study details Data source Abstract Country UK English Language Study design of participants No. 40 recruited Total: 32 of a planned 66. treated were ALA– Intervention: 16 PDT: PDT Comparator: 16 with Photofrin: of recruiting No. centres 246 period Follow-up and frequency 6 post therapy 247

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 The data This small Interpretation study is reported in abstract form in abstract form study is reported and no furtheronly publication is difficult to therefore, It is, available. assess the quality of trial and of the findings the reliability Authors’ conclusions this trial support the use of from ALA in a of the optimal regimen ALA vs Photofrin PDT RCT of Brief study appraisal 0.05) < Not assessed mth (24% risk vs 3%). The mth (24% risk vs 3%). Not assessed No patients suffered photosensitivity No patients suffered Results Mortality receiving Morbidity Patients in the group ALA–PDT and High-dose red High-dose in cancer risk light had a significant decrease with the other treatment when compared at 36 groups rates were in adenocarcinoma difference red light was compared significant when p (8% vs 45%, with green AEs oesophageal or developed reactions strictures use Resource J/cm) High-dose ALA High-dose J/cm) vs High-dose J/cm) J/cm) J/cm) vs Low-dose J/cm) vs Low-dose J/cm) mg/kg) with low-dose red red mg/kg) with low-dose mg/kg) with high-dose red mg/kg) with High-dose red or mg/kg) with High-dose red mg/kg) with high-dose red or mg/kg) with high-dose red light red mg/kg) with low-dose or mg/kg) with high-dose red Treatment details Treatment Trial treatments treatments Trial (60 light (1000 green ALA (60 light (500–700 ALA (30 light (1000 or green ALA Intervention High-dose (60 light (1000 green ALA Comparator High-dose (60 (500–700 ALA 2nd comparator Low-dose (30 light (1000 green Not Not stated Population details Population Treatment intention Treatment Not stated of cancer Type(s) and histology BO with HGD Main eligibility criteria Not stated Patient characteristics stated Concomitant treatment J/cm) – 205 RCT mth J/cm) – not 36 mg/kg) with high- 103 J/cm) – not stated mg/kg) with high-dose red mg/kg) with high-dose red red mg/kg) with low-dose Study details publications Linked Abstract Data source Country UK English Language Study design No. of participants No. to have 24 appeared Total: been randomised to either light and were or green red part of a larger study 72 patients ALA High-dose Intervention: (60 light (1000 or green not stated ALA High-dose Comparator: (60 light (500–700 stated Low-dose 2nd Comparator: ALA (30 light or green dose red (1000 centres of recruiting No. Not stated period and Follow-up frequency 246 et al. Authors Mackenzie (2007) 247

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 Interpretation Authors’ conclusions that This trial shows PDT with Photofrin is a and statistically clinically in therapy effective long-term producing ablation of HGD and the potential reducing impact of cancer with OM compared Brief study appraisal This was a RCT with blinding for procedures of outcome assessors. defined Outcomes were and appropriately AEs assessed and FU Longer-term noted. was used to trace the of dysplasia development to and progression of The results cancer. to be this trial appear with the caveat reliable being the large number centres of recruiting (and very small numbers of patients at some have sites) which may in between- resulted such site differences, as the delivery of the varying intervention (e.g. expertise in delivering have which may PDT), the overall affected The number results. at individual recruited one to sites ranged from 51 participants d . Analysis Analysis . 0.0001. 0.0001. < 0.0001). Of the 0.0001). < mth in the PHOPDT group and mth in the PHOPDT group yr compared with 30% for a 2-yr with 30% for yr compared A 2-yr responder in the PHOPDT group had a 90% in the PHOPDT group A 2-yr responder yr of FU

0.0001. Over the trial period 10% of PHOPDT patients had Over 0.0001. < yr from events unrelated to Barrett’s disease. No deaths were No deaths were disease. to Barrett’s unrelated events yr from Not assessed d, p d, Two patients in the PHOPDT and one patient in the OM group died group OM in the patient one and PHOPDT in the patients Two 0.027). There was no significant difference in squamous overgrowth overgrowth in squamous was no significant difference There 0.027). = In the initial phase of the trial, the most common AEs were AEs were the most common In the initial phase of trial, mth in the OM group. omeprazole alone responders there were 26% of the PHOPDT and 52% were there omeprazole alone responders the OM patients who terminated trial with either HGD or cancer at 10 specific time points showed groups both treatment for of responders almost twice as large in PHOPDT compared of responders a proportion was a significant There with OM at all assessment periods (data not shown). 113 PHOPDT, the median time to CR in 2 groups: between difference Results Mortality within the 1st 2 the patients who died over no additional were There to the treatment. related 3 course of the additional (complete ablation of HGD) was of responders The proportion Morbidity p higher in PHOPDT than with OM (77% vs 39%, significantly 551 and OM, HGD compared with 31% of the OM patients HGD compared of maintaining complete the probability FU period, By the end of 5-year p with 4% in OM, ablation of HGD was 48% in PHOPDT compared The median duration of the CR was 44.8 3.2 5 for chance of maintaining the response that showed the 2 groups Comparison between in the OM group. responder to cancer in progression had a significant delay patients in the PHOPDT group 21 (15%) In the PHOPDT group, with patients in the OM group. compared 20 (29%) In the OM group, d48 to 1793. to cancer from patients progressed the rate of After 5yr of FU, d63 to 1092. to cancer from patients progressed than in lower to cancer in PHOPDT was significantly patients who progressed OM ( p between groups when compared per patient or biopsy when the when compared groups between per patient. compared were of biopsies with squamous overgrowth no. average the most advanced neoplasia in any did not obscure Squamous overgrowth patient AEs All photosensitivity (36%). photosensitivity (69%) and oesophageal strictures free stricture were and 94% of patients with strictures resolved were events similar intensity were of severe Events during the course of initial phase. being PHOPDT (16%) and OM (15%) with 65% of the group for 2 years From with 2% in the OM group. compared to the treatment related none was attributed to AEs reported, no SAEs and of those were there to 5, during the long AEs occurring no photosensitivity were There the treatments. are to treatment and unrelated both related AES, Full details of all term phase. in the paper available use Resource mg PDT hr after J/cm mg of OM J/cm of diffuser d. They were told were They d. nm) applied to the nm) applied cm of BO was treated cm of BO was treated yr separated by at least yr separated by One course of PDT mth. without the cantering balloon could be given 96–120hr after PHO areas for injection but only mucosal with insufficient after the 1st light response of A maximum application. 7 during one course of PDT. that the It was required length of Barrett’s entire Patients treated. be mucosa 20 also received Treatment details Treatment treatments Trial with PHOPDT vs OM alone Intervention PHOPDT: Patients in this arm of a maximum received courses of PDT over three 5 3 consisted of a 2-mg/kg PHO injection followed one laser light session by (630 oesophageal segment with HGD 40–50 The light dose injection. was 130 length with a centring A 2nd light balloon. of 50 application Patients had to twice daily. and of eyes exposure avoid sunlight and skin to direct at high intensity light for least 30 dark sunglasses to wear a 30-d period when for outdoors Comparator OM: 20 Patients received OM twice daily 18yr. 18yr. ≥ yr 9% of Population details Population intention Treatment Curative of cancer Type(s) and histology BO with HGD Main eligibility criteria Patients were were eligible if they diagnosed with BO by with HGD proven biopsy and be Exclusion criteria were: cancer other than non- melanoma skin cancer prior within the last 5yr; PDT to the oesophagus, oesophageal strictures to unresponsive dilatation and further criteria detailed in full the paper Patient characteristics 85 % Male: 67 Mean age: Further patient characteristics were reported Concomitant treatment PHOPDT the in patients an underwent group or oesophagectomy other endoscopic 19% ablation (3%). of the patients in had the OM group PHOPDT treatment, an 10% underwent and oesophagectomy 2.9% had another endoscopic ablation technique 206–209 30 (in mth until 99 yr Authors et al. Overholt (2007) OM, omeprazole; PHOPDT, Photofrin and omeprazole. PHOPDT, omeprazole; OM, four consecutive consecutive four biopsy results negative were then HGD, for until biannually 5 248 Study details Linked publications Data source Full published paper Country Not stated Language English Study design RCT of No. participants 208 (61 in Total: long-term phase group) Intervention: 138 PHOPDT: (48 in long-term phase group) Comparator: 70 (13 in OM: long term phase group) of No. recruiting centres unnamed four countries) Follow-up period and frequency Every 3 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Interpretation Authors’ conclusions equally APC are PDT and in eradicating effective However, mucosa. Barrett’s effective PDT is more in eradicating dysplasia. Long-term FU is needed to assess cancer prevention and the durability of neosquamous epithelium. These interventions cannot for as yet be recommended practice routine Brief study appraisal This was a small trial been have that will likely to detect underpowered for differences treatment This would all outcomes. impacted on the also have analysis, cost effectiveness which accompanied this protocols Treatment trial. described but well are study methods such for as procedures randomisation and blinding The described. less well are authors advise a larger trial and also highlight the need FU longer-term for At mth: mth:

cm) mth mth: PDT mth: mth: PDT 77%; PDT 77%; mth: cm); APC 56% cm); mth. At 4 mth. cm); APC 65% (3 cm); A cost-effectiveness A cost-effectiveness 0.03) = p Not assessed Severe AEs: Severe cm) mth the incremental cost ratio was mth the incremental Results Mortality Morbidity Median length of BO eradicated at 4-mth PDT 57% (3 FU: Median length of BO eradicated at PDT 60% (3 12-mth FU: (2.5 Dysplasia eradication at 4 APC 62% ( 12 cost an additional it would i.e. £266, in reduction percentage every £266 for Full details of the using PDT. Barrett’s in provided are analysis cost-effectiveness the paper analysis was conducted from the was conducted from analysis The cost of of the UK NHS. perspective PDT per patient was calculated at £2804 The ICERs were APC £1341. and that of in cost calculated based on differences procedures the two between and effects BO length eradication and dysplasia for eradication at 4 and 12 APC was the dominant strategy being effective. and more less expensive PDT one; APC zero PDT one; AEs photosensitivity of 13 (31%), four PDT: two oesophageal stricture two; Oesophageal of 13 (23%), three APC: chest pain, severe two; stricture, hospital requiring odynophagia and fever one admission, use Resource Dysplasia eradication at 12 APC 67% NS 77%; of malignancy at 12 Development wk wk mW delivering mW delivering l/min. Depending l/min. g. Intravenous Intravenous µ g. APC was applied until a APC was applied

PDT with Photofrin vs APC PDT with Photofrin vs APC was carried out in one APC was carried

mg/kg of Photofrin was injected hr before illumination with laser. laser. with illumination before hr mg. After assessment of the Barrett’s After assessment of the Barrett’s mg. mg and fentanyl 50–100 mg and fentanyl J/cm through an endoscopically inserted an endoscopically J/cm through W and argon gas flow of 1.8 gas flow W and argon cm of the Barrett’s segment. Further treatment segment. cm of the Barrett’s Treatment details Treatment buscopan was used as an antimotility agent. buscopan was used as an antimotility agent. PDT balloon was insertedA 3-cm window and inflated after positioning, a guidewire over The laser fibre segment. adjacent to the Barrett’s was inserted into the balloon and positioned The laser light distribution. uniform to allow additional every for was repeated procedure 3 All patients were described. parameters were and ward admitted to the gastroenterology nursing The ward in a semi-dark room. nursed instructions given staff and the patients were direct avoiding leaflet about and an information 4–8 sunlight and bright indoor lights for was performed Endoscopy APC: Comparator sedation with midazolam under intravenous 5–15 using the ERBE APC was performed segment, Beamer. Argon ICC 200 setting of at a power white coagulum appeared 65 segment and on the length of Barrett’s patient tolerability, sessions with an intervalor more of 2–4 goal The treatment the sessions. between was complete ablation of BO and dysplasia of six sessions when complete or a maximum Further details were ablation was not achieved. in the paper provided Trial treatments treatments Trial Intervention 2 48 intravenously laser using 630-nm red PDT was performed output of 840 light with a power 200 was performed Endoscopy PDT balloon. sedation with midazolam under intravenous 5–15 hr mg/d, mg/d, After mg/d. mg/d. Patients mth Curative cm yr g of sucralfate every g of sucralfate every yr cm and LGD or HGD 3 hr as pain relief for 24–48 for hr as pain relief hr for retrosternal discomfort and retrosternal hr for Population details Population Treatment intention Treatment of cancer and histology Type(s) BO with LGD or HGD Main eligibility criteria with BO ≥ with histological diagnosis confirmed than 3 on biopsy no more before study entry were eligible. The eligible. study entry were before patients excluded: were following with oesophageal malignancy of oesophageal previous form, any mucosal previous resection, or endoscopic therapy ablative patients with resection, mucosal tongues rather than predominantly oesophagus, Barrett’s circumferential or patients patients with porphyria Patients intolerant to endoscopy. trying or to get pregnant pregnant, also not using contraception were excluded characteristics Patient 81 % Male: 60 Median age: 35–86 Age range: 4 Median BO length: 23(88%) 3(12%), HGD, Dysplasia: Concomitant treatment a patients received the procedures, lansoprazole 60 high-dose PPI, period and during the treatment then maintained on 30 were two All patients also received to be taken tablets of co-codamol, 6 every after the treatment. A few patients A few after the treatment. 1 also received 6 transient dysphagia mth 4 210 Not et al. et al. mth 100 Authors Ragunath (2005) and 12 Study details Linked publications Full Data source published paper Country UK English Language Study design RCT of No. participants 26 Total: PDT: Intervention: 13 APC: Comparator: 13 of recruiting No. centres stated Follow-up period and frequency 249

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 16 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Both APC and Both This small trial Authors’ conclusions half APC only PDT can ablate BO but for sessions needed treatment as many Brief study appraisal and no was reported in abstract only Many further full publication was located. of the study details and methods were the abstract and quality unclear from difficult to of the trial was therefore do not appear groups Treatment assess. comparable in terms of dysplasia Interpretation Not assessed Not assessed All patients with PDT developed All patients with PDT developed hr after treatment. 4/10 PDT patients hr after treatment. Mortality Morbidity Reduction of length was 90% APC PDT (range 0–100%) and 90% for for (range 50–100%) AEs a period of over nausea and vomiting 4 No skin transient dysphagia. showed There after PDT. was found phototoxity APC group in the was no vomiting transient but 3/10 patients developed dysphagia and one mediastinal emphysema had to be interrupted and treatment use Resource Results . . 2 J/cm mg/kg bw of ALA. ALA. mg/kg bw of PDT vs APC PDT vs W. The number of treatment treatment of number The W. sessions was four (2–9) sessions was four Number of treatment sessions was two sessions was two Number of treatment not Further PDT parameters were (1–5). reported with APC was applied APC: Comparator 70 of power a Treatment details Treatment treatments Trial 60 Intervention PDT: in the centre Cylindrical diffuser fibre and illuminated of a balloon applicator using a diode laser system with 150 yr yr Not Curative Population details Population Treatment intention of cancer Type(s) and histology Long- segment BO Main eligibility criteria Not stated Patient characteristics 65 % Male: 68 Median age: 44–77 Age range: 6/10 4/10 LGD, PDT: HGD 5/10 5/10 LGD, APC: No dysplasia Concomitant treatment stated mth, mth, mth, mth, RCT mth mth Not stated 101 Study details Abstract Data source Country Germany English Language Study design of participants No. 20 Total: PDT 10 Intervention: APC 10 Comparator: of recruiting No. centres period Follow-up and frequency Median 27 PDT: range 12–42 Median 24 APC: range 4–46 bw, body weight. bw, et al. Authors Zoepf et al. (2003) 250 251

Appendix 17 Oesophageal cancer data extraction

250 251

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Ps-PDT This study was available only as a short only study was available the methodology was not abstract, reported and it was unclear clearly to applicable were which results As a non- group. each treatment the authors’ randomised study, and strong be overly conclusions may with caution should be regarded Authors’ conclusions without a balloon centring device, and is a safe with or without EMR, for treatment curative effective highly cancer of the oesophagus/EGJ early Brief study appraisal Interpretation cm 0.67). Nine patients 0.67). Not assessed = Overall and disease Overall Not assessed EMR ( p + Six patients (7.5%) required Six patients (7.5%) required Mortality specific 5-yr survival was 88% and respectively 100%, The CR rate was Morbidity PDT alone vs 91.2% for 89.7% for PDT had a 2nd course for ablation of had a 2nd course for patients with Four HGD or cancer. Barrett’s HGD in residual new oesophageal cancers of 9–14 with PDT. successfully treated were (6.2%) subsquamous lesions Five diagnosed at FU with HGD/cancer with PDT successfully treated were chemoradiation (1) or surgery (2), (2) to normal QoL and return activity AEs vomiting, nausea, hospitalisation for transient dysphagia, dehydration, nine (11.2%) bleeding or pain); strictures. PDT-related developed no treatment-related were There deaths use Resource Results Bare fibre Ps PDT Ps fibre Bare J/cm fibre, with a 1.0, 2.5, 2.5, with a 1.0, J/cm fibre, mg/kg), then EGD plus PDT (dose mg/kg), Trial treatments treatments Trial alone vs PDT plus EMR Ps infusion Intervention PDT alone: (2 175–300 without a 5 or 7cm diffuser fibre balloon centring device) Comparator PDT with EMR: by staged and removed Lesions were 2001 to 2004 PDT from EMR before Treatment details Treatment Not Curative yr; 74 Barrett’s 74 Barrett’s yr; yr stated Treatment intention Treatment of cancer and histology Type(s) T1 oesophageal cancer Main eligibility criteria Patients with oesophageal SCC, of the oesophagus, adenocarcinoma EUS or T1 N0 M0 by EGJ staged as unfit or were CT and that refused, or declined oesophagectomy, for or declined radiation therapy, eligible were chemoradiation therapy inclusion for characteristics Patient 70 % Male: 73 Mean age: 43–91 Age range: two oesophageal carcinomas, oesophageal squamous cell cancers, junction oesophagogastric four adenocarcinomas Concomitant treatment Population details Population mth mth FU et al. et al. Non- Not stated, Not stated, wk, every 3 every wk, 107 mth. EUS and mth. mth (year 1) then mth (year CT, computerised tomography; EGD, oesophagogastroduodenoscopy; EGJ, oesophagogastric junction; EMR, endoscopic mucosal resection; EUS, endoscopic ultrasound scan; HGD, HGD, endoscopic ultrasound scan; EUS, resection; endoscopic mucosal EMR, junction; oesophagogastric EGJ, oesophagogastroduodenoscopy; EGD, computerised tomography; CT, porfimer sodium. Ps, high-grade dysplasia; Authors Canto (2005) (year 1), every 3–6 every 1), (year 2) then every (year 6–12 every CT scans taken 6 Mean 6–12 mth. every FU 31.2 mth (6–96) Study details Abstract Data source Country Not stated English Language Study design RCT of participants No. 80 Total: 58 Intervention: 22 Comparator: of recruiting No. centres 252 multicentre period Follow-up and frequency at 4–6 253

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT with 514-nm The numbers The numbers Interpretation included in this study were small and the included in this study were reported – not clearly methods were particularly in terms of comparability not The conclusions may groups. the two The majority Note: be reliable. therefore of patients in this trial had oesophageal have the results therefore tumours (14/22), been included in the oesophageal cancer group Authors’ conclusions superficial light has the potential to cure with cancer in the oesophagus and bronchi In as 630-nm PDT. the same probability deep light prevents green the oesophagus, the risk of thus reducing tissue damage, perforation Brief study appraisal Not d Not assessed Not assessed All three patients recovered with patients recovered All three

No major complications were No major complications were hr achieved a CR hr achieved Results assessed AEs Three group. observed in either treatment chest pains 630-nm PDT patients reported 10 for with associated high-grade fever Mortality Morbidity CR was seen in 9/13 of the superficial tumours (69%) with 630-nm PDT vs 6/9 tumours (67%) with 514-nm PDT. tumours three In the 630-nm PDT group in 524-nm group) a PR (vs three showed in reduced minimally and one tumour only both wavelengths In the oesophagus, size. in eradicating situ and effective were more cancer but did both cure intramucosal 2/10 tumours. than half of the submucosal at a drug–light intervaltumours treated of 1 to normal activity QoL and return the with pleural effusion, after PDT (two of oedema with endoscopic evidence 3rd and erythema on the posterior wall of of the oesophageal trachea at the level cancer). therapy antimicrobial use Resource h, h, hr. If hr. nm, nm, ) argon ) argon 2 nm with hr, three three hr, nm and five nm and five J/cm wk after drug nm: As for As for nm: nm with PDT at 630 windowed cylindrical light ° windowed (total dose 100 2 nm but using 514 mg/kg) irradiation with 630 mg/kg) irradiation nm): After injection with Photofrin nm): mW/cm hr Treatment details Treatment treatments Trial ion pumped-dye laser under general ion pumped-dye and/or cylindrical Microlens anaesthetic. used in the bronchi light distributors were and 180 or 240 tumours Ten distributors in the oesophagus. had a drug–light interval of 72 tumours had a drug–light interval of 1 was less than CR at 3-mth endoscopy, there advised to Patients were PDT was repeated. 4–6 sunlight for direct avoid administration Comparator PDT at 514 PDT at 630 tumours had a drug–light intervalfour of 1 tumours had a drug–light interval of 72 Photofrin II Intervention PDT with Photofrin (630 II (1 or 2 Photofrin II vs PDT at 514 100 yr yr Not Curative Population details Population Treatment intention of cancer Type(s) and histology Superficial oesophageal and cancers bronchial Main eligibility criteria It appeared that men and women with one or several biopsy-proven superficial SCC or of the bronchi oesophagus Patient characteristics 80 % Male: 46–79 Age range: 59.8 Age: Mean All patients had received previously and/or radiotherapy surgery primary for the of cancer invasive head and neck Concomitant treatment stated mth nm nm FU at Not 108 d, then 3 d, Authors et al. Grosjean (1998) 252 Study details Full Data source published paper Country Switzerland English Language Study design Non-RCT of No. participants 15 (22 Total: tumours) 13 Intervention: tumours (630 PDT) Nine Comparator: tumours (514 PDT) recruiting of No. centres stated Follow-up period and frequency 7–10 after treatment and twice per year thereafter 253

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT can relieve PDT can relieve This was a small Interpretation Authors’ conclusions squamous oesophageal obstruction from and is an cell and adenocarcinoma thermal necrosis to Nd:YAG alternative with a longer duration of response. patient precautions PDT requires However, to minimise skin photoreactions Brief study appraisal study and reported but well-conducted lack of blinding despite the apparent adjusted The analyses outcome assessors. and the variables, confounding for of PDT could favour significant benefits in as promising be considered 0.006), 0.006), = p mth PDT was Not assessed d vs 53 for Nd:YAG, Nd:YAG, d vs 53 for Mean survival was not wk and weight change wk and weight Not assessed In the randomised trial patients 0.001) and oesophageal grade with Nd:YAG. 0.002) compared 0.419) in dietary The difference 0.008. < = = = Results Mortality between different significantly (145 vs 128 d, PDT and Nd:YAG p At 1 Morbidity increase associated with a greater in dietary ( performance status Karnofsky performance ( p ( p with Mean duration of response PDT was 84 p at 1 levels was ns. groups treatment between PDT patients CR was seen in two vs one to normal QoL and return activity AEs relatively complications were fistula (one PDT patient vs few: skin vs two), (zero stricture two), fever vs zero), (four photoreaction vs one) and luminal plugging (five vs five) (five use Resource d W in a mW/cm PDT with DHE J/cm) red light was J/cm) red mg/kg bw), then illumination mg/kg bw), nm (300 2 ± d post injection. If there was a If there d post injection. Treatment details Treatment Trial treatments treatments Trial laser vs Nd:YAG IV DHE was Intervention PDT: (2 given laser. pumped-dye with an argon 630 fibres, cylinder-diffusing by delivered treated and tumour segments were fashion. in a retrograde sequentially density was 400 Power Tissue dose was calculated tip. fibre and light dose delivered from estimated exposed, surface area A segmental luminal diameter. from necessaryif given be could dose 2nd Patients advised to (13 patients). at least for sun exposure restrict 30 of tumour obstruction recurrence another course of PDT was given since DHE if 1 mth had elapsed injection Standard Comparator Nd:YAG: technique was used at 90 Laser pulses fashion. retrograde quartz through delivered were or coaxial air flow). (bare fibres 2–4 every was delivered Therapy until luminal patency was achieved. sessions two Most patients required Not Patients Palliative 30 mth before mth before yr yr (PDT) 73yr Nd:YAG 73yr (PDT) yr Population details Population Treatment intention Treatment of cancer and histology Type(s) Oesophageal cancer Main eligibility criteria biopsy- with dysphagia caused by oesophageal malignancy that proven had refused not suitable for, were radiotherapy or failed surgery, eligible were and chemotherapy had to Prior therapy inclusion. for ended at least 1 have Exclusion criteria enrolment. by tracheal involvement were: and Karnofsky bronchoscopy status < performance characteristics Patient 62 % Male: 42–87 Age range: 70 age: Mean both Mean Karnofsky status for 73–74 was around groups 60% of tumours were Overall, squamous and 40% were Most patients had adenocarcinoma. some kind of prior therapy Concomitant treatment stated FU Not 114 mth wk, then once wk, Authors Heier et (1995) al. Study details Full Data source published paper Country USA e English Languag Study design RCT of No. participants 42 Total: 22 Intervention: 20 Comparator: of recruiting No. centres CT per month. 3 every stated period Follow-up and frequency at 1 254 not significant. ns, ethers; dihaematoporphyrin DHE, 255

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT when Few Few Interpretation methodological and patient details were reported in this abstract of a small study of the conclusions is so the reliability to have The authors appear unclear. with the conclusions at odds drawn statistical test results from conclusions do not follow The authors’ reportedthe results Authors’ conclusions in indicated as a salvage therapy after CRT patients with local failure oesophageal cancer tended to be for than when indicated as less effective severe Moreover, a 1st-line treatment. including death-related complications, more significantly were procedures after prior in patients treated frequent CRT Brief study appraisal

0.015) (two strictures strictures 0.015) (two = Not assessed Not assessed 0.3. There was no difference in was no difference There 0.3. = Severe complications were 10% in complications were Severe Results Mortality Morbidity 16/22 lesions (73%) were in the primary treated successfully vs 8/15 (53%) after failed intent group p CRT, (9 vs groups rate between recurrence ns) 14%, to normal activity QoL and return Not assessed AEs the primary vs 50% intent PDT group ( p failed CRT for requiring endoscopic dilation vs two endoscopic dilation vs two requiring requiring strictures and five perforations Death rate directly dilation respectively). to PDT was 0% in primaryrelated intent (ns) failed CRT patients vs 14% for use Resource mg/kg), illumination mg/kg), PDT in patients Treatment details Treatment treatments Trial in primarytreated intent vs PDT in with PDT after local patients treated CRT of definitive failure Intervention Primary intent PDT: After IV Photofrin (2 The 48h. laser between with a dye of PDT sessions was mean number endoscopies with routine Control 1.18. planned 6–8 wk after PDT. biopsies were reported No further details were As Comparato r PDT after failed CRT: primaryfor intent PDT except mean of PDT sessions was 1.33 number

Not Curative Population details Population Treatment intention of cancer Type(s) and histology Early stage oesophageal cancer Main eligibility criteria Not stated Patient characteristics in Not reported states no paper detail, significant differences groups. between Median tumour length 2cm Concomitant treatment stated Non-RCT Median FU 111 mth Study details Abstract Data source Country Not stated English Language Study design of participants No. 35 (37 lesions) Total: lesions) (22 21 Intervention: (primary intent PDT) 14 (15 Comparator: lesions) (PDT indicated of CRT) after local failure centres recruiting of No. Not stated period and Follow-up frequency 15 et al. et al. Authors Lecleire (2008) not significant. ns, chemoradiotherapy; CRT, 254 255

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT with The methods Interpretation were generally well-described though well-described generally were not reported. were features a few been useful to gauge have It may opinion of ease patient/investigator and importance of of treatment the photosensitivity to QoL inform conclusions Authors’ conclusions equal overall porfimer solution has laser thermal efficacy to Nd:YAG palliation of dysphagia ablation for and equal or in oesophageal cancer, tumour response better objective photosensitivity is a Temporary rate. out with but PDT is carried limitation, ease and is associated with greater than Nd:YAG acute perforations fewer laser therapy Brief study appraisal

0.05). 0.05). cm and in < 10 wk and 60% mth, none mth, Not assessed 0.05). Data was obtained 0.05). mth (PDT –0.75 vs < Not assessed 0.05). All PDT patients were All PDT patients were 0.05). < p Significantly more PDT patients more Significantly wk (PDT –0.73 vs Nd:YAG wk (PDT –0.73 vs Nd:YAG mth ( p showed analyses Subgroup mth. wk and 32% PDT vs 20% Nd:YAG wk and 32% PDT vs 20% Nd:YAG Results Mortality Morbidity Dysphagia grades baseline from improved significantly at 1 –0.90) and 1 –0.68) with both treatments Nd:YAG treatment between (ns difference tumour response Objective groups). patients with CR or PR) (responders: (ns) at was 44% PDT vs 48% Nd:YAG 1 at 1 at 1 but groups between ns differences of PDT in favour was a trend there rates tumour response objective for of the third in the upper and lower tumours > oesophagus, prior therapy. patients that received between was no difference There patients with squamous cell for groups cancer and adenocarcinoma activity normal to return and QoL from 80% patients at 1 from Not assessed AEs p AE (92% vs 82%, had an nausea (8% Sunburn (19% PDT vs 0%), (16% vs 5%) and pleural fever vs 2%), significantly effusion (10% vs 2%) were PDT and oesophageal for greater (1% Nd:YAG for greater perforation vs 7%) severe. Treatment-related respiratory Treatment-related severe. in 3% PDT (vs insufficiency occurred for equal overall AEs were Severe 1%). both treatments use Resource photosensitive for 1–2 for photosensitive W s was hr after d patients were d patients were PDT vs Nd:YAG PDT vs Nd:YAG mW/cm, total dose mW/cm, nm) provided by a by nm) provided mg/kg bw), illumination by illumination by mg/kg bw), J/cm). After 2–3 J/cm). Treatment details Treatment Trial treatments treatments Trial laser 40–50 Intervention PDT: injection with single intravenous Ps (2 light (630 red pumped-dye argon wave continuous via an optical laser and delivered quartz with a cylindrical fibre diffusing tip (400 300 to debride the necrotic re-endoscoped tumour could tumour and residual of with a 2nd application be treated of A maximum laser light (same dose). courses at 1-mth intervalsthree was permitted laser therapy: Comparator Nd:YAG setting of 15–90 A laser power and pulse duration of 0.5–4.0 with either contact used (delivered or non-contact technique via quartz Each session ended when fibres). the endoscopist thought maximum patient benefit or maximum achievable Repeat sessions tolerance was reached. if initial response could be given was deemed insufficient (the course was deemed complete when the dysphagia had believed investigator been palliated or further therapy be futile) would yr cm; cm; Not wk before wk before Patients Palliative yr; Nd:YAG 72 Nd:YAG yr; cm Population details Population intention Treatment of cancer and histology Type(s) Oesophageal carcinoma Main eligibility criteria oesophageal with a biopsy-proven too malignancy and that were failed to refused, debilitated for, to or had a recurrence respond radiation chemotherapy, following eligible for or surgery were therapy Also patients with SCC inclusion. and that were or adenocarcinoma, had malignancy-caused symptomatic, and a dysphagia to solid foods Karnofsky status of at least 30% were was required Prior therapy eligible. to be terminated at least 4 was Bronchoscopy randomisation. tumours at or above for required Patients with of the carina. the level of the tracheobronchial involvement and those that had prior tree oesophageal carcinoma for treatment laser were with PDT or Nd:YAG radiation and Concurrent excluded. not permitted were chemotherapy characteristics Patient 72 % Male: PDT 68 Median age: Median Karnofsky performance status: status: Median Karnofsky performance 80% 45% Prior therapy: PDT 6 Median tumour length: Nd:YAG 5 Nd:YAG had the rest 51%, Adenocarcinoma SCC Concomitant treatment stated FU mth 24 112 wk, then 1, then 1, wk, Study details Data source Full published paper Country USA e Languag English Study design RCT of No. participants 236 (218 Total: treated) Intervention: 118 (110 treated) Comparator: 118 (108 treated) of No. recruiting centres at 1 3 and 6 2, Follow-up Follow-up period and frequency Authors Lightdale et al. (1995) 256 not significant. ns, 257

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Combined This was a Interpretation Authors’ conclusions approach new a represents PDT/HBO of oesophageal and in the treatment to have which appears cancer, cardial enhanced the efficacy of PDT Brief study appraisal despite not small pilot study that, does seem to have being randomised, comparison reasonable achieved The authors comment that groups. randomisation was not possible due of the to the variable availability The conclusions chamber. oxygen but the study would reasonable are blinded outcome benefited from have assessors mm mth 0.43). At 0.43). cm PDT vs = 0.002 = mth). Stenting with mth). mth, dysphagia score dysphagia score mth, Not assessed d (five vs nine). Six vs nine). d (five 0.065. Mean decrease Mean decrease 0.065. = mth. One patient had mth. 0.021) y Median survivalMedian y PDT after (five vs nine) and chest ° (five A semi-solid diet was = No major complications related No major complications related mm in the PDT group vs 6.3 mm in the PDT group p cm PDT/HBO, mth) and four cases (PDT/HBO mth) and four mth and two PDT/HBO patients mth and two mth, mean decrease in stenosis was mean decrease mth, Results 3 5.6 p PDT/HBO, in tumour length was 2 2.8 Mortalit PDT/ was 8.7 mth vs 13.8 for HBO ( p At 3 Morbidity but in both groups had decreased was no significant difference there ( p treatments between to normal QoL and return activity possible in all patients after PDT or PDT/HBO AEs HBO and photosensitisation, to PDT, of the ear or and no barotrauma lung or sunburn was observed. Minor complications included: postinterventional odynophagia fever (eight PDT vs nine PDT/HBO), up to 39 1 or 2 pain for were fistulas oesophagotracheal cases (PDT at 5 and in two found 17 14 and 24 7, at 4, coated, self-expandable stents was coated, in one PDT patient at performed 16 at 14 and 17 of the tumour 18 haemorrhage after PDT/HBO use Resource nm levels levels 2 o hr, PDT, PDT, hr, P PDT vs mmHg. Before Before mmHg. J/cm of fibre, 630 J/cm of fibre, mth if necessary but most d after PDT, endoscopy was endoscopy d after PDT, mg/kg) was administered mg/kg) was administered applied by a KTP-Nd:YAG laser. laser. a KTP-Nd:YAG by applied was under short- Treatment anaesthesia. term intravenous 2–3 tissue and necrotic repeated, if necessary. mechanically removed could be repeated Treatment after 3 one session patients received Comparator PDT under HBO PDT but As for (PDT/HBO): ATA of 2 under HBO at a level Oxygen chamber. in a hyperbaric with the Scuba was administered transcutaneous valve, Trial treatments treatments Trial under HBO Photosan-3 Intervention PDT: (2 After 48 intravenously. with a 1-cm tip radial using a fibre was inserted light-diffusing cylinder, Illumination using an endoscope. dose was 300 Treatment details Treatment were 500–750 were nose and patients had an ear, HBO, check-up throat Before Before It appeared It appeared Palliative yr yr PDT, 12 (seven in PDT, five in PDT/ five in PDT, 12 (seven PDT, dilatation HBO) patients underwent laser Nd:YAG and retrograde disobliteration Population details Population judged Most patients’ cancers were dysphagia scores to be stage III, 3 and 4 no 2, levels varied across were at baseline significant differences SCC in 25 cases, were Tumours found. Further in 25 cases. adenocarcinoma reported patient characteristics were Concomitant treatment that patients with advanced cancer tract of the upper gastrointestinal resection not eligible for who were due to poor performance treatment functional and/or anatomic status, and/or anatomic inoperability, surgery and/or refusing inoperability, inclusion eligible for were characteristics Patient 81 % Male: 46–87 Age range: 67.3 Mean age: Treatment intention Treatment of cancer and histology Type(s) Advanced cancer of the upper tract gastrointestinal Main eligibility criteria mth FU at Non- Not stated 115 mth, then every 3 then every mth, Study details Full Data source published paper Austria Countr y e English Languag Study design RCT of participants No. 52 Total: 23 (PDT) Intervention: 29 (PDT Comparator: under HBO) of recruiting No. centres Follow-up period Follow-up and frequency 1 et al. Authors Maier et al. (2000) 256 absolute. atmosphere ATA, 257

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Combined This , although the authors were not although the authors were , Interpretation Authors’ conclusions a new PDT/HBO represents of in the treatment approach cancer oesophageal and cardial enhanced the to have which appears efficiency of PDT Brief study appraisal study was not randomised (and been subject to have so may small bias) and included a fairly The authors of patients. number that did though acknowledge conclusions could not be definitive This based on these results. drawn to be the same publication appears of a pilot study study as a report 211 explicit about this At d (four in d (four d) 0.0064). No 0.0064). cm in the PDT/HBO = p mm ° in the afternoon of mth in PDT/HBO group), mth in PDT/HBO group), mth, stenosis decreased in stenosis decreased mth, d (median 4.9 cm vs 3 Hospitalisation in both Median overall survival with PDT Median overall 0.0002 = mth (vs 12 There were no major postinterventional were There 0.0098. 12-mth survival with PDT was 0.0098. = Results p 25% vs 52% with PDT/HBO At 3 Morbidity 6 by both groups median tumour length In the PDT group was 2 decrease p group, At 3-mth FU (or last in case of death) could be dysphagia score in the PDT group in eight cases (vs nine) one level by lowered in 23 cases (vs 33) (and levels and two by it could be lowered the PDT/HBO group this significantly cases); in two levels three PDT/HBO ( favoured dysphagia was observed at 3-mth recurrent either group FU for to normal activity QoL and return least a semi-solid diet was possible in all patients after either treatment AEs complications or skin photosensitisation No barotrauma to either treatment. related Minor complications included: was observed. 6 vs PDT/HBO odynophagia (PDT group up to 39 fever 8); in one in PDT vs three interventional day, 1 or 2 chest pain for PDT/HBO); mortality 30-day in PDT/HBO). PDT vs seven fistulas in two Six oesophagotracheal was 0%. PDT/ cases; two (PDT, found patients were cases) HBO four use Resource was 3–9 groups Mortality was 7 hr PDT vs d after PDT nm applied nm applied J/cm, 630 J/cm, wk. PDT given 48 PDT given wk. mg/kg) and camouflage wk, then sunblock for then sunblock for wk, Treatment details Treatment Trial treatments treatments Trial PDT/HBO Intervention PDT: intravenously HpD given (2 used for skin protection 2 10 after sensitisation with radial (1-cm tip, a fibre light diffusing cylinder) the biopsy inserted through channel of the endoscope placements were (several Light dose was necessary). 300 laser with a KTP-Nd:YAG Treatment box. with DYE under short-term given was Endoscopy anaesthesia. 2–3 repeated tissue removed and necrotic if necessary. mechanically dilatation and Prior to PDT, was Nd:YAG retrograde necessary in 15 cases Comparator PDT/ PDT except As for HBO: nose patients had ear, then check-up, and throat under HBO (2 PDT given in a walk-in atmospheres) chamber hyperbaric yr; yr; Not yr Cancer Population details Population Treatment intention Treatment stated of cancer and Type(s) histology Advanced oesophageal carcinoma Main eligibility criteria not eligible Patients that were due to treatment resection for were significant comorbidity included characteristics Patient 80 % Male: 67 PDT alone, Mean age: PDT/HBO 67.5 46–87 Age range: 16 Dysphagia IV, 59; III, stage: 3, level 23; 2, level score: 35 40 SCC, 15. 4, level 37; adenocarcinoma Further patient characteristics reported were Concomitant treatment Not stated mth, mth, 211 Non-RCT mth FU after 1 116 et al. Authors Maier et al. (2000) then every 3 then every 258 Study details publications Linked Full published Data source paper Austria Country English Language Study design of participants No. 75 Total: 31 Intervention: 44 Comparator: centres of recruiting No. One period and Follow-up frequency 259

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT has A Authors’ conclusions to be an effective been shown of advanced treatment palliative However, oesophageal cancer. patient selection is proper serious necessary to prevent complications Brief study appraisal of patients sizeable proportion pre-treated were in each group which did not with Nd:YAG, in to be accounted for appear This trial appears the analysis. separate contained four to have although this was poorly arms, Patients in good/ described. a slightly fair condition received protocol. treatment different it difficult These limitations make of the reliability to evaluate authors’ conclusions Interpretation

0.0129) 0.0001). 0.0001). = = mth for mth for mth p mth PDT mth brachytherapy and mth brachytherapy mth PDT, brachytherapy brachytherapy mth PDT, d after PDT, spontaneous d after PDT, Not assessed Mean survival was 5.6 0.28 = Major complications occurred in 9% Major complications occurred 0.0003). The mean increase in opening The mean increase 0.0003). d = mth, p mth, Mortality 7.7 brachytherapy; 6.3 external beam irradiation; 13 brachytherapy; was a There and external beam irradiation. with PDT* ( p significant difference ( and external beam irradiation* This was biased, as groups without external as groups This was biased, contained patients that beam irradiation regimen. entering the irradiation died before (Authors’ comment.) these *It was unclear which patient groups to referred results improved Morbidity Dysphagia score and levels one to three in all patients by in the PDT group greater was significantly ( p stenosis was diameter of tumour-related with in the PDT group greater significantly than in or without external beam irradiation conditions either of the brachytherapy to normal activity QoL and return no significant differences were There in terms of groups the two between at status scores Karnofsky performance 3 AEs including oesophageal (11/119) of patients, severe after brachytherapy, perforation 3 haemorrhaging of distal oesophagus with perforation fistula and oesophagomediastinopleural 5 pleural emphysema concurrent after PDT, tracheo-oesophageal or after PDT, Due to strictures, fistula. tracheobronchial dilation was necessary after PDT (four After (45 patients). patients) and Nd:YAG odynophagia for PDT 28 patients reported 2–5 use Resource Results 80 nm mth. mth. 80 (fair d between d between Gy per session J/cm fibre, 630 J/cm fibre, mth, then every 3 then every mth, PDT and brachytherapy PDT and brachytherapy hr PDT treatment using hr PDT treatment d after PDT, endoscopy repeated repeated endoscopy d after PDT, d between sessions. This process was This process sessions. d between Gy Gy mg/kg), after 48 mg/kg), Gy per session was given, patients received patients received Gy per session was given, applied by a KTP-Nd:YAG laser with DYE- a KTP-Nd:YAG by applied 2–3 box). Endoscopy tissue removed. and necrotic after 1 was performed within 3 PDT was not repeated mth. was given Iridium-192 brachyradiotherapy insertionby of the afterloading catheter. 5 sessions in total depending on one to four with endoscopic findings and dysphagia, 3–7 out under short-termcarried intravenous combined with topical anaesthesia, In 25 anaesthesia with supported breathing. of > patients with Karnofsky score was completed by condition) treatment using the multiple external beam irradiation mean dose of field technique to deliver 44 Iridium-192 : Comparator Brachytherapy insertion by was given brachyradiotherapy 5 of the afterloading catheter. one to four patients received was given, sessions in total depending on endoscopic with 3–7 findings and dysphagia, was done under short- This process sessions. combined with anaesthesia, term intravenous topical anaesthesia with supported breathing. of > In 17 patients with Karnofsky score was completed by (fair condition) treatment using the multiple external beam irradiation mean dose of field technique to deliver 44 Treatment details Treatment treatments Trial alone vs brachytherapy Intervention PDT and brachytherapy: was haematoporphyrin Intravenous (mean 1.5 injections/patient) administered (2 with 2-cm radial light-diffusing a fibre biopsy channel of cylinder inserted through an endoscope (dose 300 yr; yr; yr yr Population details Population intention Treatment Palliative of cancer and Type(s) histology Advanced oesophageal carcinoma Main eligibility criteria not Patients who were due resection eligible for of to tumour involvement poor the adjacent tissue, status plus performance result a as status inoperable of refusal of comorbidity, or a surgical intervention, were combination of these, included characteristics Patient 81 % Male: 67 Men, Age: Mean 65 women 27–93 Age Range: 80; III, Cancer stage: 68 SCC and 51 39. IV, adenocarcinoma Further patient characteristics were reported treatment Concomitant 21 patients therapy to Prior initial dilatation required and tumour obliteration with Nd:YAG FU Non- Not stated 117 mth, then every then every mth, mth Study details Full Data source published paper Austria Country e English Languag Study design RCT of participants No. 119 Total: Intervention: 44 (PDT and brachyradiotherapy) 75 Comparator: (brachyradiotherapy) of recruiting No. centres 3 Follow-up period Follow-up and frequency at 1 258 Authors Maier et al. (2000) 259

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Despite the limitations The conclusions that Interpretation Authors’ conclusions photosensitisation of a non-randomised study, effective with Photosan seems to be more in PDT of advanced oesophageal carcinoma ALA with compared Brief study appraisal limited as this was a small, were could be drawn Baseline characteristics non-randomised study. M stage and the similar apart largely from were reliable. authors’ cautious conclusions appear been published twice to have This study appears 120) with Photosan being described (see ref. and results treatments The patients, as HpD. one study only therefore to be identical, appear has been data extracted 0.02), 0.02), = 0.000014) p = 0.00000) d (nine vs p = p mth vs 9mth, mth vs 9mth, mth, there was there mth, Hospitalisation 0.12) = Median survival for ° in the afternoon of d in both treatment d in both treatment Karnovsky Performance Performance Karnovsky No barotrauma of No barotrauma 0.44 (Kaplan–Meier survival0.44 (Kaplan–Meier = Results Mortality was 8 ALA group p curve in paper) At 1 Morbidity improvement more significantly than the ALA group in the the following for Photosan group dysphagia ( outcomes: QoL and return to normal QoL and return activity 23% for by status improved not Photosan, ALA vs 44% for significant ( p AEs No the ear was observed. in either sunburn occurred no major were There group. mortality was 0%. 30-day AEs. Minor complications were: postinterventional odynophagia fever vs 13); ALA group (nine in up to 39 vs eight); (five interventional day 1 or 2 chest pain for ALA administration all After 13). patients experienced nausea use Resource was 4–6 groups tumour stenosis ( and tumour length ( hr mth. mth. mth after hr. 6–8 hr. J/cm fibre J/cm fibre mg/kg) then skin hr before PDT hr before ALA- PDT vs with mth, then every 3 then every mth, d after PDT and necrotic d after PDT and necrotic mg/kg), 48 mg/kg), after ALA, PDT was carried out using a fibre out using a fibre PDT was carried ALA, after with 2-cm tip radial light-diffusing cylinder, the biopsy channel of inserted through Light dose was 300 endoscope. Trial treatments treatments Trial with Both performed Photosan (HpD). oxygenation hyperbaric additional Diagnostic ALA–PDT: Intervention using barium was performed work-up oesophagogastroscopy, oesophagogram, Oral and CT scans. bronchoscopy ALA (60 administration of for 24 camouflage by protection KTP-Nd: by and 630-nm light was applied Additional module. a DYE laser having YAG was applied oxygenation hyperbaric check-up) nose and throat (after an ear, system. using a Scuba valve ATA 2 at level under short-term was performed Treatment was Endoscopy anaesthesia. intravenous 2–3 performed was then Endoscopy tissue removed. after 1 performed tumour length and dysphagia at Increased No FU indicated further PDT treatment. within 3 was repeated treatment the 1st PDT session ALA– As for Comparator Photosan-PDT: administration of PDT except intravenous Photosan (2 Treatment details Treatment yr; yr; yr yr Not stated Population details Population intention Treatment Palliative of cancer and Type(s) histology Advanced oesophageal cancer Main eligibility criteria Patients that not eligible for were due treatment resection to poor performance functional and/or status, anatomical inoperability, surgeryand/or refusing included were characteristics Patient 78 % Male: 46–88 Age range: 69 ALA, Mean age: Photosan 68 Cancer stage: III, 17; IV 17; III, Cancer stage: Dysphagia score 32. varied with most in level 2 or 3 but no significant differences 13 were there Overall 14 adenocarcinoma SCC, Further patient characteristics were reported Concomitant treatment FU 120 Not 118 mth, then every then every mth, mth 3 Study details Linked publications Full Data source published paper Country Austria English Language Study design Non-RCT of No. participants 49 Total: 22 Intervention: (ALA–PDT) 27 Comparator: (Photosan-PDT) of recruiting No. centres stated period Follow-up and frequency at 1 Authors Maier et (2001) al. 260 absolute. atmosphere ATA, 261

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 ° ° or 240 PDT eradicates This was a nm instead of red light at 630 nm instead of red nm). Stenoses always result result Stenoses always nm). Authors’ conclusions T1b) of the SCCs (T1a and early Transmural oesophagus efficiently. leading to fistulas can be necroses using a low-penetrating avoided light of laser light (green wavelength at 514.5 or 652 of irradiation circumferential from and this can the oesophageal wall, using a 180 by be avoided small trial with multiple relatively the methods were comparator arms, reported and as the authors not clearly comment – the small themselves firm conclusions, any samples preclude not be reliable may so the results windowed cylindrical light distributor windowed Brief study appraisal Interpretation 75%. 75%. nm) = 89%, 89%, h) some = mth; 2 mth; hr. With hr. Not assessed nm; 3/16 (19%) for 3/16 (19%) for nm; Not assessed 86%, Photofrin II 86%, = Not assessed mg/kg mTHPC patients at All patients reported nm d) mTHPC patients had necroses that were that were patients had necroses HpD CR rates: selective. according of treatment Failures 1/9 to sensitiser used were 2/8 (11%) in the HpD group; 2/14 (25%) Photofrin II group; Failures (14%) mTHPC group. to according of treatment 2/15 (13%) used were wavelength 630 or 652 for 514 to normal QoL and return activity AEs burning sensation during the Major injection of mTHPC. Stenoses complications were: fistulas oesophagotracheal (two), in PDT patients (630 or 652 one of which complicated (two, Three oesophageal stenosis). by patients that did not follow (not in precautions prescribed 2nd-degree methods) developed sunburn on the face and hands (one HpD patient at 2 0.15 6 use Resource mTHPC (irradiation at 96 mTHPC (irradiation Mortality selective Morbidity No truly was seen with HpD, necrosis Photofrin II or mTHPC when was at 20 irradiation Results , , min. min. 2 nm, nm, nm) nm) nm) J/cm mg/kg nm, nm, nm, 6 or nm, ] for 19 ] for 2 windowed ° windowed hr (630 nm, 30 nm, mg/kg (652 hr (514 mg/kg (514 mg/kg), then mg/kg), mg/kg (514 hr (652 min. Surface min. mW/cm ° or 240 min. Surface min. windowed cylindrical ° windowed cylindrical ° windowed nm) PDT vs mTHPC hr (514 min. Surface irradiation Surface irradiation min. , 90 , 2 ) for 21 ) for 2 mm diameter) was used ) for 14 ) for J/cm 2 HpD PDT vs Photofrin II ) for 3 ) for 2 windowed cylindrical light ° windowed mg/kg (652 nm (most patients) or 514nm, nm (most patients) or 514nm, mg/kg), then PDT given with an then PDT given mg/kg), nm) PDT vs mTHPC 0.15 mW/cm ) for 10 min. Surface irradiation using Surface irradiation 10 min. ) for mW/cm 2 mW/cm , 80 , 2 hr [630 , 90 , 2 , 40 , 2 mg/kg), then PDT given with an argon with an argon then PDT given mg/kg), mg/kg), then PDT given with an argon ion with an argon then PDT given mg/kg), nm) PDT mg/kg), then PDT given with a argon ion with a argon then PDT given mg/kg), J/cm mg/kg (514 mW/cm J/cm J/cm mean light dose 100 irradiation using 180 or 240 irradiation light distributors (15 intravenous Comparator Photofrin II PDT: Photofrin II was injected (1 or 2 laser ion pumped-dye with an argon PDT given after 72 using 180 or 240 used distributors (15-mm diameter) were comparator mTHPC 0.3 3rd mTHPC was injected intravenous PDT: (0.3 laser after 20 pumped-dye using 180 or 240 irradiation light distributors (15-mm diameter) was used Treatment details Treatment Surface irradiation using 180 Surface irradiation cylindrical light distributors (15-mm diameter) was used 2nd comparator mTHPC 0.15 mTHPC was injected Intravenous PDT: (0.15 laser after 20 ion pumped-dye 8 cylindrical light distributors 180 or 240 windowed (15-mm diameter) was used 4th comparator mTHPC 0.15 50 PDT: intravenous mTHPC was injected intravenous PDT: (0.15 laser after 20 or 96 pumped-dye 75 Trial treatments treatments Trial vs mTHPC 0.15 0.3 (514 HpD Intravenous Intervention HpD PDT: was injected (3 laser after 72 ion pumped-dye argon 100 yr yr None Curative Population details Population Type(s) of cancer Type(s) and histology SCC of the Early oesophagus Main eligibility criteria Biopsy confirmed early Patients with SCC. were porphyria excluded Patient characteristics 92 % Male: 42–79 Age range: 56 Mean age: patients Twenty-two had a history of head primary invasive two and neck cancer, had no such history. patients had Two tumours, synchronous patients developed five early metachronous cancers Concomitant treatment Treatment Treatment intention nm) nm) nm) FU at Non- Not stated mth, then 6-mth mth, 109 mg/kg with 652 mg/kg with 514 mg/kg with 514 d, 3 d, Study details Full Data source published paper Country Switzerland English Language Study design RCT of participants No. 24 (31 tumours) Total: Nine Intervention: tumours (HpD-PDT) Eight Comparator: tumours (Photofrin II- PDT) Two 2nd Comparator: tumours (mTHPC-PDT, 0.15 et al. et al. Authors Savary (1998) 3rd Comparator: One Comparator: 3rd tumour (mTHPC-PDT, 0.3 4th Comparator: 11 4th Comparator: tumours (mTHPC-PDT, 0.15 Follow-up period Follow-up and frequency 10 260 of recruiting No. centres intervals 261

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 In poor This small Authors’ conclusions surgical candidates with superficial PDT oesophageal carcinoma outcomes and EMR achieved in comparable to oesophagectomy PDT and surgical candidates. good to alternatives reasonable EMR are selected patients for oesophagectomy Brief study appraisal as an abstract only study was available methodological details were and few the The study populations for reported. interventions did not appear different to be comparable at baseline with PDT/ EMR patients chosen if suboptimal for no statistical tests In addition surgery. the findings, out to verify carried were therefore of this study may the results not be reliable conclusions do not follow The authors’ reported the results from Interpretation

Not assessed Not assessed Stricture occurred in 6/12 occurred Stricture 3 dilatations occurred in 4/12 3 dilatations occurred Results Mortality Morbidity Eradication of lesions was 5/6 (83%) in 9/12 (75%) PDT, achieved EMR and 18/19 (95%) oesophagectomy patients to normal activity QoL and return Not assessed AEs 0/6 EMR and 10/19 (50%) PDT, patients. (53%) oesophagectomy ≥ 0/6 EMR and 7/19 (37%) (33%) PDT, Other patients. oesophagectomy small reported for complications were of patients numbers use Resource PDT vs EMR Treatment details Treatment treatments Trial Oesophagectomy No details Intervention PDT: reported No details Comparator EMR: reported 2nd comparator Oesophagectomy: No details reported Mean Not stated Population details Population Treatment intention Treatment Curative of cancer Type(s) and histology Superficial oesophageal cancer Main eligibility criteria Superficial oesophageal cancer EUS determined by and CT including HGD, in situ or carcinoma carcinoma intramucosal Patient characteristics 73; EMR, 76; PDT, age: 65 oesophagectomy, Thirty-six one adenocarcinomas, SCC Concomitant treatment mth wk Non-RCT mth). PDT and mth). Mean FU 15 110 mth; oesophagectomy oesophagectomy mth; Study details Abstract Data source Country USA English Language Study design of participants No. 37 Total: 12 (PDT) Intervention: Six EMR Comparator: 19 2nd Comparator: (oesophagectomy) centres of recruiting No. Not stated period and Follow-up frequency EMR, endoscopic mucosal resection. endoscopic mucosal EMR, (range 2–28 EMR patient FU 4–6 then every after treatment, 3–6 patient FU dictated by symptoms 262 Authors Scotiniotis et al. (2000) 263

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Radiotherapy Radiotherapy This was a Authors’ conclusions combined with PDT could obviously enhance the long-term survival rate of patients with advanced oesophageal cancer Brief study appraisal brief report and some methodological reported. not clearly aspects were not reported The p -values were the abstract and between consistently the text making it difficult to clarify groups between significant differences Interpretation

d d 10 Not assessed The 5-yr survival rate was 0.05). The 10-yr survival rate 0.05). = All PDT patients experienced 0.05) < Mortality with compared 29.9% in the PDT group 16.7% ( p vs 10.0% was 16.7% in the PDT group ( p Morbidity Not assessed to normal activity QoL and return Not assessed AEs and itchiness. and swelling pigmentation, All PDT patients also experienced 3–5 for pain when swallowing > (some patients had pain for 23 died treatment). and discontinued loss to FU two; in the PDT group: localisation 13 including uncontrolled one due to blockage of oesophagus; other disease one; metastases eight; 26 died in the cause one. unknown loss to FU one; group: radiotherapy including localisation 18, uncontrolled due to blockage of oesophagus; two other disease two; metastases four; cause two unknown use Resource Results Gy for Gy for Gy). Then Gy). hr PDT with wk (40 mg/kg bw) before mg/kg bw) before at each part of the tumour 2 min) at 48 and 72 W/cm wk for 15 for 40 Comparator Radiotherapy: 4 Treatment details Treatment treatments Trial alone vs radiotherapy radiotherapy Intervention PDT with radiotherapy: 4 for Radiotherapy haematoporphyrin intravenous (5 derivative light (400– illumination with 630-nm red 500

cm. No cm. yr Treatment intention Treatment Palliative of cancer and Type(s) histology Advanced oesophageal cancer Main eligibility criteria Diagnosed with advanced suitable oesophageal cancer, treatment for characteristics Patient under 70 Age: 5–10 Cancer length: metastases Concomitant treatment Not stated Population details Population FU at et al. et al. RCT One hospital yr 119 Authors Zhang (2003) (outpatients) period Follow-up and frequency 5 and 10 No. of participants No. 60 Total: 30 Intervention: 30 Comparator: of recruiting No. centres 262 Study details Full Data source published paper Country China Chinese Language Study design 263

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 17 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT is safe and PDT is safe This study Interpretation method of reported (e.g. was poorly was whether ITT analysis randomisation, that used) but most importantly it appears 40 patients had been treated, after over out and all was carried interim analysis with treated subsequent patients were These analyses combined PDT and 5-FU. this shift Given not further reported. were an RCT to experimental without a from comparator it is difficult to determine the overall of the study results reliability from conclusions do not follow The authors’ reportedthe results Authors’ conclusions advanced oesophagocardiac for effective can be further effect Its therapeutic cancer. when combined with local improved chemotherapy Brief study appraisal

mth mth 0.05), 0.05), 0.05). 0.05). < < 0.01) < p Not assessed Mean survival time was 8.9 Subternal pain due to oesophageal d after treatment was reported by by was reported d after treatment Mortality with 15.1 with PDT alone compared for PDT and 5-FU ( for Results The rate of dysphagia Morbidity PDT compared was 87% for remission with 99% PDT and 5-FU ( p in pharyngeal pain and weight Differences With PDT alone not significant. loss were complete remission one patient achieved p with combined therapy, (vs five remission (vs 36) and five eight significant With combined (vs nine). no remission minor 48 patients also achieved therapy remission to normal activity QoL and return Not assessed AEs injury reflux mucosa and gastroesophageal 1–2 and eight patients in PDT only seven patients in combination treatment exposed Eight patients in total accidentally to sunlight and developed themselves discoloration of the skin No oesophageal stenosis or perforation reported in either group use Resource hr with either mg/kg bw) and mth PDT vs with 5-FU J/cm fibre length, median length, J/cm fibre mg 5-FU was locally injected into mg 5-FU was locally nm high power He-Ne laser (total nm high power mth unless evaluation showed showed mth unless evaluation J/cm). This was delivered by cylindrical by This was delivered J/cm). PDT: After intravenous After intravenous Intervention PDT: injection of the photosensitiser PSD-007 (3–5 (photocarcinorin) Trial treatments treatments Trial Irradiation in the dark. kept patients were at 24 and 48 was performed laser pumped-dye 630-nm copper vapour or 632.8 As for Comparator PDT with 5-FU: irradiation, before PDT but in addition, 200–500 dose 200–400 300 diffusers under endoscope assistance. out in one to four was carried Irradiation between segments (with slight overlap each segment) depending on lesion length could be repeated Treatment and diffuser. after 1 remitted. or symptoms were effectiveness sunlight advised to avoid Patients were 1 over for exposure tumour tissue under endoscopic guidance. injection the extent of lesions Before four received patients Most confirmed. was to eight injections per tumour Treatment details Treatment yr Not Palliative Treatment Treatment intention of cancer Type(s) and histology Advanced oesophagocardiac carcinoma Main eligibility criteria Biopsy advanced proven oesophageal carcinoma Patient characteristics 79 % Male: 40–81 Age range: PDT 58; Median age: PDT with 5-FU 62 Stage Cancer stage: stage III 53; II 84; stage IV 3 Concomitant treatment stated Population details Population FU et al. et al. RCT mth Not stated; Not stated; 113 mth. Over 70% Over mth. Study details Full Data source published paper Country China English Language Study design of participants No. 140 Total: 42 Intervention: 98 Comparator: of recruiting No. centres followed patients were 12–36 up for appears to be two to be two appears in China centres period Follow-up and frequency at 1 264 Authors Zhang (2007) 265

Appendix 18 Lung cancer data extraction

264 265

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 18 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 No conclusions This small Authors’ conclusions specific to PDT Brief study appraisal of a RCT study was an interim analysis Although in abstract form. presented would it indicated that updated results no further information be presented, Most of the study’s could be located. not methodological details were the abstract and from available not broken were majority of the results group treatment by down Interpretation Assessed but not reported Assessed but not reported Minor haemoptysis in two PDT- Minor haemoptysis in two Mortality per group Morbidity Not assessed AEs Skin photosensitivity was patients. ERT with PDT acceptable in patients treated AEs reported Other (no data provided). group by down but not broken Results wk before wk before Gy at 1-cm mg/kg, mg/kg, ERT: As ERT: + wk before ERT. ERT. wk before ERT alone vs PDT ERT Gy to the tumour area Gy to the tumour area nm given 2 nm given 2.5 x 8 + 2.5 J/cm, 630 J/cm, wk x Other PDT parameters not stated alone: Comparator ERT 14 in 4 2nd comparator HDR 15 HDR: by preceded above distance along the tumour 2 ERT Treatment details Treatment treatments Trial ERT vs HDR preceding ERT preceding Intervention Photofrin 2 200 10% 70% Not stated Population details Population intention Treatment Palliative of Lung Cancer Type and Histology Non-small no further details cell; given Main eligibility criteria proven Histologically inoperable locoregional loss < weight NSCLC, and a PS (sic) > characteristics Patient 88 % Male: Concomitant treatment RCT et al. et al. Not stated Not stated 121 Study details Abstract Data source Country The Netherlands English Language Study design of participants No. 39 Total: 15 Intervention: 12 Comparator: 12 2nd Comparator: of Recruiting No. Centres period and Follow-up frequency 266 Authors Baas (1994) 267

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 18 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 mth PDT is a valid method of Difficult to evaluate Difficult to Interpretation Authors’ conclusions palliation in partially obstructing NSCLC or totally Brief study appraisal due to important baseline differences results and stage of cancer) between of cough, (presence 1 after FU and performance Karnofsky groups. No details on blinding assessed but not reported. d mth in ns). PR ns). d (PDT) vs 38 = 0.03) mth ( p = Survival significantly Assessed but not reported 0.007). 4/14 (PDT) and 4/17 0.007). Bronchitis was the most Bronchitis mth in three PDT and four PDT and four mth in three = Results Mortality (265 vs 95 longer in PDT group p d, (Nd:YAG) still alive at end of study still alive (Nd:YAG) in Morbidity Similar response 38.5% PDT vs 23.5% both groups: at 1 Nd:YAG at 1 CR at 1 patients. Nd:YAG until Time elapsed one PDT patient. 50 failure: treatment ( p (Nd:YAG) to normal QoL and return activity AEs cases in PDT group, common (four group) one in Nd:YAG PDT Photosensitisation in four AEs, patients had no Five patients. One death group. all in Nd:YAG to PDT related probably s. s. hr d as necessary mg/kg with 630-nm Trial treatments treatments Trial laser PDT vs Nd:YAG resection Intervention DHE at dose Intravenous of 2 40–50 laser, dye argon Maximum after injection. doses (six of three Other photoradiations). parameters not reported Comparator Nd:YAG using 15- to resection 80-W pulses of 0.5–1.5 repeated Procedure 2–4 every Treatment details Treatment wk 3 ≥ Not wk from wk from Biopsy- 4 Palliative yr, non- yr, 40%, ≥ 40%, 18 ≥ yr last chemotherapy cycle and last chemotherapy Patients who last radiation dose. from were PDT or Nd:YAG had previous Further eligibility criteria excluded. reported were characteristics Patient 100 % Male: Not stated Age range: 65 Mean age: patients; four Stage I, Cancer stage: stage IIIB, six; stage IIIA, one; stage II, seven stage IV, 10; three tumour: with recurrent No. Concomitant treatment stated Population details Population intention Treatment of Lung Cancer and Types Histology Non-small cell 25 three adenocarcinoma, three SCC, carcinoma undifferentiated Main eligibility criteria inoperable cancer with totally proven endobronchial or partially obstructive without extrabronchial with or lesions Patients > tumour. pregnant, infertile or postmenopausal. infertile or postmenopausal. pregnant, Karnofsky status 122 mth if Not stated mth (and 18 Follow-up period Follow-up and frequency 6 and 3, 2, FU at 1, 12 Study details Full Data source published paper Country Spain English Language Study Design RCT of participants No. 31 Total: 14 Intervention: 17 Comparator: of Recruiting No. Centres possible) 266 Authors Diaz- (1999) Jimenez et al. 267

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 18 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Authors’ conclusions of PDT prior The addition provides to radiotherapy better and significantly local control longer-lasting alone than radiotherapy Brief study appraisal No details of methods allocation randomisation, concealment or blinding this small reported for were study (raising reliability Some outcomes issues). assessed but not reported Interpretation 0.05) d in < 0.005) = d, p d, radiotherapy radiotherapy Assessed but + radiotherapy radiotherapy + d vs 107 d in Radiotherapy-alone d in Radiotherapy-alone radiotherapy group ( p group radiotherapy + radiotherapy and 2/21 radiotherapy and 2/21 radiotherapy radiotherapy + 16 patients died in radiotherapy-alone 16 patients died in radiotherapy-alone radiotherapy vs 445 radiotherapy radiotherapy group radiotherapy (233 group radiotherapy radiotherapy group radiotherapy mth, in the PDT mth, + + + + Photosensitivity with mild erythema, which Photosensitivity with mild erythema, d, respectively, after treatment), compared with compared after treatment), respectively, d, group, in both groups eight deaths were due to eight deaths were in both groups group, patients in the PDT Three metastases. 187 and haemoptysis (67, massive died from group 567 No difference group. none in the Radiotherapy-alone in median survival groups times (444 between PDT group) reduction of greater Morbidity Significantly and cough at 1 haemoptysis and shortness of breath, and 3 14/20 PDT alone achieved complete re-opening of bronchial of bronchial complete re-opening alone achieved group patients in Radiotherapy-alone Four lumen. none failed in to treatment, failed to respond PDT and Median interval treatment between longer in was significantly local recurrence PDT QoL and return to normal activity QoL and return not reported (Karnofsky performance) AEs of the was seen in four without treatment, resolved PDT Results Mortality with 14 in PDT compared group J/cm. J/cm. mW/cm, mW/cm, mg/kg followed mg/kg followed cm into tumour). cm into tumour). hr of red (630nm) hr of red wk, using a parallel pair wk, radiotherapy vs radiotherapy cGy in 10 fractions with + Treatment details Treatment Trial treatments treatments Trial PDT alone Radiotherapy Intervention Intravenous Photofrin at 2 with 40–50 laser argon-dye light from a single-step index by delivered quartz inserted fibre into the biopsy channel of a flexible (a bronchoscope fibreoptic cylindrical diffuser tip was inserted 1–2 density was 400 Power total light dose was 200 a by Residual tumour treated light exposure repeat The duration of light was not – see Radiotherapy stated. below Comparator Radiation at 3000 a 4-MeV linear accelerator 2 over by Field size defined technique. the 50% isodose line with 2-cm margin of normal tissue See Palliative yr 40 and ability to ≥ Population details Population intention Treatment of Lung Cancer Types and Histology Non-small three cell 34 squamous cell, large cell four adenocarcinoma, Main eligibility criteria stage III non-small Biopsy-proven carcinoma cell bronchogenic with obstructing or partially lesion. obstructing endobronchial Karnofsky rating bronchoscopies. tolerate multiple PDT Patients who had previous or concurrent or radiotherapy, laser or Nd:YAG chemotherapy as were excluded, were therapy patients whose tumours were on to major blood vessels invasive CT scan characteristics Patient 76 % Male: 67 Around Mean age: 78% in main stem location: Tumour 22% in lobar bronchus bronchus, Concomitant treatment ‘Eligibility criteria’ FU RCT Not stated 123 mth at 1, 2, 3, 6, 12, 18 and 18 12, 6, 3, 2, 1, at 24 Study details Full Data source published paper Country Canada English Language Study design of participants No. 41 Total: 20 Intervention: 21 Comparator: of Recruiting No. Centres period Follow-up and frequency 268 Authors Lam et al. , (1991) 269

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 18 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 The addition The addition Very small Very Authors’ conclusions provides of PDT prior to radiotherapy better and longer- significantly than radiotherapy lasting palliation, patients with obstructive for alone, The combined tumours. endobronchial survival also improve may treatment Brief study appraisal sample size coupled with poorly it difficult to reported methods make conclusions robust any draw Interpretation wk 0.05) in < 0.05) < wk, but the wk, wk, the wk, 0.05). There There 0.05). < radiotherapy radiotherapy + At 4 wk (with mean 0.05) when compared 0.05) when compared < p One patient died in the 0.05). The mean score The mean score 0.05). < radiotherapy patients had radiotherapy radiotherapy group vs three in vs three group radiotherapy and 7 group, radiotherapy had a mean group radiotherapy wk (99 vs 25, p wk (99 vs 25, + + + + wk, the PDT wk, One patient receiving PDT One patient receiving PDT ( p significant improvements both Karnofsky rating (78 vs 93) and to baseline compared QoL (56 vs 39), no significant were There scores. in the Radiotherapy-alone differences group AEs 8 for photosensitive remained Mortality PDT group the Radiotherapy-alone had Morbidity Both groups respiratory improved significantly symptoms at 4 7 to 1 in the falling from scores PDT to 4 in the Radiotherapy-alone p group, group the Radiotherapy-alone for was back up to 7 at 12 PDT which was significantly of 2, score baseline ( p from different At 4 reduction in% had a significant group obstruction (99 vs 21) and airway in arterial (63 oxygen improvement both vs 80, airway with percentage to baseline, improved obstruction still significantly at 12 were no significant reductions in the no significant were group Radiotherapy-alone to QoL and return normal activity Results nm) wk radiotherapy radiotherapy d later, with d later, + mW/cm and J/cm. Clean-up J/cm. PDT J/cm (but no more J/cm (but no more at power density of at power 2 wk of PDT J/cm using microlens fibre using microlens 2 hr prior to red light (630 hr prior to red cGy in 10 fractions over 2 cGy in 10 fractions over mW/cm cm) was inserted into the tumour. cm) was inserted into the tumour. MeV linear accelerator. Field size MeV linear accelerator. The dose of Photofrin and duration radiotherapy, For not stated. light were see below All patients had Comparator 3000 using a parallel-pair technique from a 4 by the 50% isodose line with defined 2-cm margin of normal tissue 200 Treatment details Treatment treatments Trial alone vs Radiotherapy Photofrin Intervention Intravenous II 24–48 pumped-dye argon a continuous from via single-step index quartz fibres laser, inserted into channel of a double bronchoscope lumen flexible fibreoptic A (or a single channel instrument). 1.0 or cylindrical diffuser tip (0.5, 1.5 density was 400 Power total light dose 300 2 followed bronchoscopy further light at 300 tumours. residual any Photofrin II) for with radiotherapy 1st, PDT was given starting within 1 that could not be inserted Tumours or hardness, due to small size, 200 received yr Population details Population intention Treatment Palliative of Lung Cancer Types and Histology Non-small two nine squamous cell, cell: large cell Main eligibility criteria Patients with inoperable non-small cell bronchogenic partially or carcinoma, obstructing a completely who had central airway, no prior treatment received or chemotherapy (e.g. Patients radiotherapy). of metastatic with evidence excluded disease were characteristics Patient 82 % Male: 66 Mean age: All patients had tumours at than one site more Concomitant treatment Not stated RCT FU at 4 and Not stated 124 wk, then quarterly wk, et al. Authors Lam et al. (1987) Study details Full Data source published paper Country Canada English Language Study design of participants No. 11 Total: Five Intervention: Six Comparator: of Recruiting No. Centres period and Follow-up frequency 12 (unless thereafter of tumour progression occurs) 268 269

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 18 1 1 and mth Photofrin is at The very following treatment following Brief study appraisal provided, limited information particularly on study methods and on no numbers (e.g. basic results group) treatment randomisation by difficult assessment of reliability makes Interpretation Authors’ conclusions least similar to or better than Nd:YAG the thermal ablation in re-establishing patency of the obstructed lumen and palliating symptoms at wk

PR comparable + mth PDT also improved mth PDT also improved Not assessed Mild-to-moderate skin mth (PDT 61% vs Nd:YAG 35%, 35%, mth (PDT 61% vs Nd:YAG 0.05). At 1 0.05). < Results Mortality Morbidity CR at wk 1 (PDT 65% vs groups between different but significantly 61%), Nd:YAG at 1 p symptoms of dyspnoea (28% vs 13%), haemoptysis (33% cough (33% vs 11%), (22% vs and sputum production vs 19%), p -values not stated 14%), to normal activity QoL and return Not assessed AEs photosensitivity in 21% of PDT patients. No further details PDT vs Nd:YAG PDT vs Nd:YAG mg/kg of Photofrin hr later by light activation hr later by Treatment details Treatment treatments Trial laser Intervention 2 48 followed wavelength and duration, Light source total light dose, density, power of light, and of sessions allowed, no. maximum advice not stated postoperative Comparator No details provided Not Not Palliative Population details Population Treatment Treatment intention of Lung Type Cancer and Histology Non-small cell Main eligibility criteria Not stated Patient characteristics stated Concomitant treatment stated wk and 212 RCT FU at 1 Not stated 125 mth Study details publications Linked Abstract Data source Country Not stated English Language Study design of participants No. 141 Total: Not stated Intervention: Not stated Comparator: of Recruiting No. Centres period and Follow-up frequency 1 270 et al. Authors Leroy (1998) DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Photosan This small wk after PDT patients pilot study was non-randomised and at baseline had differences the groups impacted on results. have which may The survival data do not solely of the PDT the effectiveness reflect as 4 treatment, a variety eligible to receive were also are There of other treatments. ALA dosage doubts as to whether the was optimal Authors’ conclusions ALA than effective seems to be more in PDT of malignant tracheobronchial would these results However, stenosis. need confirming in a randomised, blinded trial Brief study appraisal Interpretation 0.020) = mth and the mth ( p d (6 in the ALA group ALA group d (6 in the wk FU The mean survival for 0.00015). One patient had 0.00015). = Mean Karnofsky value No sunburn occurred in either No sunburn occurred 0.00073, in favour of Photosan. of Photosan. in favour 0.00073, = Photosan group 14 Photosan group Morbidity 4 stenosis diameter ALA group, In the a mean value of 79% from dropped the In the Photosan group to 63%. 50% to 19%, from mean value dropped p ALA in 10/16 Dyspnoea was improved patients and 19/24 Photosan patients. ALA Haemoptysis subsided in 13/16 patients and 20/24 Photosan patients. Radiological and clinical signs of poststenotic pneumonia subsided in ALA patients and 9/13 Photosan 5/9 was no statistically There patients. groups between significant difference on pulmonary function parameters to normal QoL and return activity ALA 78 to 79 in the changed from 70 to 78 in the and from group, a significant showing Photosan group, of the Photosan in favour difference ( p group Mortality was 9 ALA group the ALA of 10% in the an improvement 11 patients in the whereas group, 10% by improved Photosan group None of by 20%. improved and five the patients in Photosan group in QoL due to reported a decrease skin protection long-lasting need for AEs No major complications group. PDT to photosensitisation, relating Minor observed. or HBO were in the fever complications were: ALA group, afternoon after PDT (12 in and mild chest 18 in Photosan group) 1 or 2 pain for None and 13 in the Photosan group). specific treatment AEs required of the Results mg/kg, mg/kg, . Light . 2 J/cm hr prior to PDT. hr prior to PDT. PDT with 5-ALA mg/kg, 48 mg/kg, nm was applied by a KTP-Nd: a KTP-Nd: by nm was applied hr after photosensitisation wk hr prior to PDT at 630 In module. laser with a DYE YAG hyperbaric additional both groups in ATA of 2 at a level oxygenation chamber was a walk-in hyperbaric Oxygen was applied undertaken. Each system. using a Scuba valve under was performed treatment anaesthesia short-term intravenous with endotracheal intubation Skin and spontaneous breathing. use of a was managed by protection Italy) Milan, camouflage (Covermark, 24 for Comparator Photosan-3 was at a intravenously administered dosage of 2 See interventiondetails of PDT for using was by Skin protection delivery. sun blocker available a commercially 12 for Treatment details Treatment Trial treatments treatments Trial and HBO vs PDT with Photosan HBO ALA was orally Intervention at a dose of 60 administered 6–8 tumour stenosis, In cases of severe using a fibre out by PDT was carried with a 2-cm tip radial light-diffusing which was inserted through cylinder, the biopsy channel of endoscope. In cases of moderate tumour stenosis system a 2-cm balloon applicator homogeneous light was used for the During treatment distribution. radial light diffusing cylinder and/or system was closely balloon applicator to the surface of tumour. applied The light dose was 100 At Patients Palliative yr; Photosan, Photosan, yr; wk after combined PDT/ yr Population details Population Treatment intention Treatment of Lung Cancer and Type Histology Non-small cell Main eligibility criteria with malignant tracheobronchial resection not eligible for stenosis, because of poor treatment functional and/ status, performance and/or or anatomical inoperability, surgeryrefusing characteristics Patient 75 % Male: 64 ALA, Mean age: 66 Stage seven; Stage IIb, Cancer stage: 14 Stage IV, six; Stage IIIb, 13; IIIa, Adenocarcinoma Squamous cell 27, three Large cell carcinoma 10, 79% ALA, Stenosis mean (range): 50% (20–95%) Photosan, (50–90%); 22 patients with radiological and clinical signs of poststenotic pneumonia Karnofsky status mean (range): 70 Photosan, 78 (60–90); ALA, (60–80) Further patient characteristics reported were Concomitant treatment least 4 considered all patients were HBO, including furtherfor treatment, high-dose rate brachyradiotherapy, and/or external beam irradiation chemotherapy wk 1 Non- One 127 wk ATA, atmosphere absolute. atmosphere ATA, Study details Full Data source published paper Austria Country English Language Study design RCT of participants No. 40 Total: 16 Intervention: 24 Comparator: of Recruiting No. Centres period Follow-up and frequency and 4 et al. Authors Maier et al. (2002) 271

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 18 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT is A small Authors’ conclusions in than Nd:YAG effective more obstructive patients with extensive lung cancer Brief study appraisal study with no details of methods allocation of randomisation, concealment or blinding (raising issues) reliability Interpretation , 0.35 , 1 0.05 mth < 0.0006. Both FVC 0.0006. < No treatment-related No treatment-related improved significantly more more significantly improved 1 No serious post-treatment No serious post-treatment 0.05, mean difference in FEV mean difference 0.05, < with PDT 1 mth after treatment with PDT 1 mth after treatment to pre-treatment when compared in mean difference measurements: 0.47 PDT vs –0.06 Nd:YAG, FVC, p PDT vs 0.01 Nd:YAG, p PDT vs 0.01 Nd:YAG, All patients had a PR at 1 AEs in Mild fever complications. No patients. Nd:YAG two photosensitivity in PDT patients Results and FEV Mortality mortality not Longer-term mortality. assessed luminal At 1-mth, Morbidity of normal as percentage diameter, in greater was significantly diameter, (83%) than the Nd:YAG PDT group p (61%), group s. Dose s. mg/kg PDT vs Nd:YAG PDT vs Nd:YAG s. Further sessions s. hr later by red light red hr later by mW/cm. Duration of mW/cm. W pulses of 3–5 nm) from a copper vapour a copper vapour nm) from J/cm at 400 Treatment details Treatment Trial treatments treatments Trial laser Photofrin Intervention Intravenous or Photofrin II at dose of 2 48–54 followed (630 through laser delivered pumped-dye with a a 600-nm quartz fibre Dose of terminal cylindrical diffuser. 200 light dose was 500 Thorough if needed. provided after debridement and physiotherapy counselling on Careful treatment. photosensitivity laser Comparator Nd:YAG Pilkington) with a 100, (Fibrelase 400- µ m diameter delivery fibre using 40–50 dependent on extent of tumour. if needed Further sessions provided 50% Some Stage Palliative yr mth Population details Population intention Treatment of Lung Cancer and Type Histology Non-small cell Main eligibility criteria III inoperable NSCLC with > intraluminal bronchial obstruction intraluminal bronchial characteristics Patient 81 % Male: 43–76 Age range: Intervention 60, Mean age: comparator 66 (ns) Concomitant treatment patients had additional modalities of patients had additional after 1 treatment et At 1, At 1, RCT Not stated 126 mth, then at mth, Study details Full Data source published paper Country UK English Language Study design of participants No. 26 Total: 15 Intervention: 11 Comparator: of Recruiting No. Centres period Follow-up and frequency 2 and 3 intervals3-monthly Authors Moghissi al. (1993) 272 273

Appendix 19 Biliary tract cancer data extraction

272 273

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 19 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT has the This study Interpretation Authors’ conclusions prolong potential to considerably survival bile duct in non-resectable is not dependent The effect cancer. on the type of haematoporphyrin photosensitiser Brief study appraisal was reported in abstract form details of and did not provide only methodology such as randomisation, blinding and allocation concealment. be This is a small trial which may to detect a difference underpowered the photosensitisers between NS = d (95% CI 448 Not assessed Median survival in the Not assessed There was no substantial There d (95% CI 84 to 903), p d (95% CI 84 to 903), Mortality was 690 PS-3 group to 931) and in the PF2 group it was to 931) and in the PF2 group 494 Morbidity Not assessed to normal QoL and return activity AEs observed (no data skin reaction 23% of patients in the PF2 provided). and 26% of patients in the group ‘considerable’ developed PS3 group cholangitis use Resource Results W, W, PDT with hr before hr before mg/kg Photofrin mg/kg Photosan-3 hr before radiation. radiation. hr before wk. Further PDT wk. Further PDT wk. A 4-cm quartzand fibre

J/cm). Light protection was Light protection J/cm). J/cm). Light protection was Light protection J/cm). W, 220 W, 220 4–6 advised for not reported parameters were Comparator 2 48 II administered radiation. 1, a diode laser system (635 nm; 1 4–6 advised for not reported parameters were Treatment details Treatment treatments Trial Photosan-3 vs PDT with Photofrin II Intervention 2 48 administered A 4-cm quartzand a diode fibre 1 1, laser system (635 nm;

Palliative Population details Population intention Treatment of Cancer and Type(s) Histology bile duct cancer Non-resectable Main Eligibility Criteria Advanced bile duct cancer (no further details given) characteristics Patient 76 % Male: 67–70 Median age: Histological confirmation was not reported Concomitant treatment antibiotic Peri-interventional prophylaxis Non-RCT Not stated Not stated 132 Study details Abstract Data source Country Not stated English Language Study design of participants No. 29 Total: 16 Intervention: 13 Comparator: of recruiting No. centres Follow-up period and Follow-up frequency 274 Authors Dechene et al. (2007) 275

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 19 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Interpretation Authors’ conclusions ERCP with PDT seems to increase survival in patients with unresectable cholangiocarcinoma with when compared although it ERCP alone, to be proved remains whether this is due to or PDT or the number ERCP sessions Brief study appraisal The aims of this study at its inception are uncertain as the study but began in 2001, became PDT only use in for available this point From 2004. PDT was offered on, making to all patients, recruit it difficult to with similar groups baseline characteristics. the authors However, that the acknowledged study design prevented conclusions definitive being drawn from 0.0001 0.01), 0.01), = = p mth (0% Not mth, SD mth, 0.08) vs Stent- = mth when compared mth when compared 0.008 for PDT and 0.008 for 0.003. Mortality rates were Mortality rates were 0.003. = < 0.78) Not assessed = mth (56% vs 82%, p mth (56% vs 82%, 0.01), and 6mth (16% vs 52%, p and 6mth (16% vs 52%, 0.01), At end of study 10 patients were still At end of study 10 patients were = Stent-alone group: 10 patients developed 10 patients developed Stent-alone group: mth, SD 1.6), p SD 1.6), mth, Results Mortality the PDT group eight being from alive, significant prolonged was statistically There survival (mean 16.2 in the PDT group 2.4) compared with the Stent-alone group (mean with the Stent-alone group 2.4) compared 7.4 significantly lower in the PDT group at 3 in the PDT group lower significantly p vs 28%, but not at 12 alone group decreased significantly had groups Both Morbidity of serum bilirubin at 3 levels ( p to baseline levels for stent only), although there was no significant although there stent only), for in the degree groups the two between difference ( p of decrease to normal activity QoL and return assessed AEs patients dying as a cholangitis (with two pancreatitis patients developed Four consequence). Further results and one had duodenal perforation. patients experienced three PDT group: reported. patients developed Seven skin phototoxicity. and two cholecystitis, developed two cholangitis, Furtherreported results haemobilia. use Resource and 2 W/cm replaced replaced hr prior to nm* with a nm in the paper, based nm in the paper, mg/kg 48 , fluence of 0.25 , 2 ERCP with PDT and stent vs J/cm s. One or two segments treated segments treated One or two s. 3-nm) light from a 2000-mW diode 3-nm) light from Treatment details Treatment laser, delivered through a 3-m length fibre having having a 3-m length fibre through delivered laser, a 2.5-cm-long cylindrical diffuser at distal end (diffuser was inserted into a 10F sheath of plastic stent) at 633 Photoactivation performed light dose of 180 Trial treatments treatments Trial ERCP with Stent alone of all decompression Intervention Selective dilated segments was attempted with opacified, bougie and balloon dilatation to assist in the stents placement of polyethylene Photofrin at 2 Intravenous 633-nm (± duration of 750 at PDT repeated of endoscopist. at discretion 3-mth intervals when all stents were to have on the type of laser used this appears error been a typographic of all decompression Comparator Selective dilated segments was attempted with opacified, bougie and balloon dilatation to assist in the 8.5F and stents (7F, placement of polyethylene Repeated if indicated until 10F in diameter). or death patient refusal (this was done earlier if premature occlusion or (this was done earlier if premature migration occurred) *Although reported as 620 yr yr Population details Population Treatment intention Treatment Palliative of cancer and Type(s) histology Non-resectable cholangiocarcinoma Main eligibility criteria after PDT offered Unclear, December 2004 to all non-resectable with patients or cholangiocarcinoma lesions deemed resectable inoperable characteristics Patient 50 % Male: 26–94 Age range: 66.6 Mean age: Bismuth extension: Tumour 19%; II, Bismuth 6%; I, Bismuth 35%; III, Bismuth 40% IV, Further patient characteristics were reported Pathological diagnosis was confirmed in 69% of cases Concomitant treatment patients had Twenty-two and 19 had chemotherapy All patients radiotherapy. periprocedure received antibiotic prophylaxis

FU at 133 One mth and every mth and every mth thereafter Authors Kahaleh (2008) et al. Study details Full Data source published paper Country USA Study design Non-RCT of No. participants 48 Total: 19 Intervention: 29 Comparator: of recruiting No. centres Follow-up period and frequency 1 3 (or earlier if were there complications) 274 a stent. size’ of the sheath used to introduce ‘French The F, 275

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 19 This Interpretation Authors’ conclusions to PDT added best supportive improves care survival and QoL in patients with Prolonged NCC. survival time was not associated with a high rate AEs of Brief study appraisal was a well- conducted and reported trial, which was halted due to the early superiority of the PDT treatment d 21% 3.8, 3.8, = 0.001) improved 0.001) improved < The Karnofsky 0.21 (95% CI 0.12 to = 0.01). After PDT physical After PDT physical 0.01). < d in the Stenting-only group group d in the Stenting-only 0.0001. RR 0.0001. < p 3.7 0.01) and global QoL ( p Not assessed = < Median survival was 493 in the PDT group 0.001). Photosensitivity was reported by by Photosensitivity was reported 0.001). < Stenting group and the Stenting-alone group was and the Stenting-alone group Stenting group + Burden of treatment was lower in PDT vs Stenting was lower of treatment Burden 0.01). Successful drainage was obtained in 72% 0.01). < Results Mortality (95% CI 276 to 710) and 98 (95% CI 87 to 107) index improved after PDT with a median 80% score after PDT with a median 80% score index improved mean change from 100%); maximum 50%, (minimum in the Stenting-alone baseline 3.00 but did not improve the baseline between in change from The difference group. PDT p 11.43 (95% CI 2.92 to 19.95, functioning ( p The but not in the Stenting-alone group. in the PDT group are to QoL measures of individual factors relating results listed in the paper AEs alone ( p of patients in both groups. After PDT serum bilirubin of patients in both groups. to baseline and stenting relative levels lower reached ( p PDT group of stent exchanges: Mean number stenting alone to normal activity QoL and return mild and were all reactions (10%) of PDT patients; two during FU cholangitis occurring Any completely. resolved cases in the PDT three were There AE. an was considered Stenosis in the Stenting-alone group. and seven group in the two by was reported to therapy related probably Fatal in the Stenting-alone group. and zero PDT group PDT group to therapy: related sepsis possibly cholangitis, six of 19 Stenting-alone group of 18, two not related causes of death probably were The following to therapy: alone Stenting 18, of one group PDT Pulmonaryembolism: of 19 three Stenting one of 19 one of 18, PDT group Cachexia: respectively one of 19, one of 18, failure: Cardiac respectively eight of 19, 12 of 18, Metastases: respectively of 19, zero one of 18, failure: renal Chronic use Resource 0.35). Two patients in the PDT group were still alive at the still alive were patients in the PDT group Two 0.35). due to the study was terminated early time of evaluation. the superiority of PDT in Morbidity Successful drainage was achieved , , s 2 J/cm Stenting 50% within d). At least two At least two d). hr before laser hr before mg twice daily mg twice daily m. Photoactivation was µ m. Double stenting vs + min (minimum 40; maximum maximum 40; min (minimum and irradiation time of 750 and irradiation 2 PDT mth. Eight patients received Eight patients received mth. nm using a light dose of 180 W/cm d after injection and thereafter d after injection and thereafter mm, core diameter 400 core mm, mg/kg body wt intravenously 48 mg/kg body wt intravenously d after stenting. When the 1st procedure did When the 1st procedure d after stenting. Treatment details Treatment treatments Trial alone details of stenting. Intervention See comparator for Photofrin at a dosage of PDT patients received 2 and removed were Endoprostheses activation. Cotton set catheter an endoscopic Huibregtse the strictures. above proximally was introduced with a Intraluminal photoactivation was performed length with a cylindrical diffuser tip, laser quartz fibre 40 at 630 performed fluence of 0.241 under a continuous saline perfusion. A new set of A new saline perfusion. under a continuous was inserted after completion of endoprostheses are Further technical details of the procedure PDT. in a darkened Patients remained in the paper. available 3–4 for room FU If any to light. adapted gradually patients were of tumour in the bile evidence examination showed of treatments Mean number PDT was repeated. duct, the mean no of 5), maximum 1, was 2.4 (minimum illuminations per patient was 5.3 and the median time was 79 treatment via a nasal catheter to oxygen All patients received 180). optimise the PDT effect Comparator Endoscopic double-stenting diagnostic ERCP (all patients received followed 250 therapy oral ciprofloxacin 14 for ERCP and continued before the had to be placed above 10F endoprostheses Endoscopic plastic patient. in every main strictures plastic prostheses or percutaneous endoprostheses Successful drainage after technically used. were was in paper) successful stenting (definition given > in bilirubin level defined as a decrease 7 a 2nd successful stenting, not lead to technically When the 2nd procedure was performed. procedure stenting was percutaneous was not satisfactory, after randomised only Patients were performed. Stent exchanges were successful stenting. technically 3 every performed three; PDT, four; extra interventions (chemotherapy, treatment one) as a last resort immunotherapy, Oral d 30%. 30%. mg Palliative mth previously mth previously yr of age with a proximal yr of age with a proximal cm in diameter), imaging- cm in diameter), 3 Population details Population intention Treatment of cancer and Type(s) histology NCC Main eligibility criteria patients at Inclusion criteria were least 18 malignant tumour of the bile TNM types II–IV, ducts (Bismuth had a large They stages III and IV). (> tumour non-resectable confirmed, independent two (assessed by histology and positive surgeons), of cancer another no evidence Exclusion criteria were organ. chemotherapy previous porphyria, previous or radiotherapy, successful stenting technically insertion of a (details in paper), partialof resection metal stent, diagnostic cholangiocarcinoma, than 1 ERCP more and a Karnofsky index of < in the Further detail is presented paper characteristics Patient Not stated % Male: 53–85 Age range: Intervention 64; Median age: 68 (NS) control seven; Stage III, Cancer stage: stage IVb 13 19; stage IVa, 31 IV, six; III, two; II, type: Bismuth 100% of all cases were confirmed histologically Further patient characteristics reported were Concomitant treatment 250 therapy, ciprofloxacin was started before twice daily, 14 for ERCP and continued d, d, 14 134 Two mth after mth, 6 mth, Authors Ortner (2003) et al. Study details Data source Full published paper Country Germany Language English Study design RCT of No. participants 39 Total: 20 Intervention: 19 Comparator: of No. recruiting centres 3 the intervention. Survivors then up at followed 6-mth intervals Follow-up Follow-up period and frequency 276 cholangiocarcinoma. non-resectable NCC, DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Stenting + Interpretation Authors’ conclusions complete tumour Only including hepatic resection, enables long-term resection, survival patients with for hilar cholangiocarcinoma. PDT Palliative in longer survivalresulted than stenting alone and has a similar survival time with incomplete compared R1 and R2 resection Brief study appraisal No firm conclusions the from can be drawn of this study for results was There reasons. several of treatments heterogeneity groups within the three some patients in (e.g. also group the resection neoadjuvant PDT). received also were The groups heterogeneous clinically different (significantly several at baseline for was and there parameters), wide variation in length of and groups FU between patients mg/dl mth, mth, mth d for d for d for d for mth, median mth, At 3 mth vs 6.4 stenting compared with stenting compared + 0.01) < mth. Neoadjuvant PDT before Neoadjuvant PDT before mth. Stenting group + stenting and Stenting alone: At 3 stenting and Stenting alone: d for stenting alone, and 48 stenting alone, d for stenting vs Stenting alone:1- and stenting group had significantly lower lower had significantly stenting group Stenting and decreased by 8% in by Stenting and decreased + + + 0.05). Successful drainage achieved in Successful drainage achieved 0.05). Median hospital stays were 65 were Median hospital stays + < stenting group, there was a significant there stenting group, stenting/Stenting alone: There were no were There stenting/Stenting alone: + PDT + Stenting patients and 32 Stenting-alone 44 stenting, mg/dl, p mg/dl, + + PDT 0.01); 63(93%) vs 51(91%) patients had died by 63(93%) vs 51(91%) patients had died by 0.01); 0.001). PDT 0.001). < < ( p tumour the end of study (the main causes were cholangitis). and complications of chronic progression 8.3% and death rates were The 30- and 60-day Resection: infective from Multiple organ failure respectively. 11.7%, complications was the most common cause of death. 3- and 5-yr survival rates including post 1-, Overall with respectively, 40% and 27%, 73%, op deaths were a median survival of 23 3- and 5-yr survival rates of 88%, in 1-, resulted resection 28% and 19% after with 66%, 42% and compared in was no significant difference There surgery alone (ns). median survival the (R1 and R2) resection time between and the PDT group Morbidity PDT Results Mortality 51% and 16% vs 23% 10%, 2-yr survival rates were median survival time 12 respectively; in the PDT to baseline relative in mean bilirubin levels difference ( p levels of bilirubin than the Stenting-alone group (4.1 group Stenting-alone the than bilirubin of levels vs 7.3 PDT 75% of patients receiving in 27 Recurrence Resection: stenting alone. 39% receiving patients to normal activity QoL and return status increased Karnofsky performance pre-treatment PDT 2% for by ( p Stenting-alone group AEs Eight PDT patients had skin deaths. procedure-related Bacterial cholangitis seen in 38 (grades I and II). toxicity PDT in 52% of major complications reported Resection: (ns). The most common relaparotomy). patients (37% required complication was bile leakage (eight patients) use Resource PDT resection d. d. mth mg/kg with stenting vs Stenting Intravenous stenting: + + Trial treatments treatments Trial PDT alone vs Resection Intervention PDT Photofrin at 2 photoactivation after 1–4 Repeated when there of tumour was evidence Further PDT progression. not parameters were for See below reported. stenting At Comparator Stenting: 9F or 11.5F plastic least two placed were endoprostheses the main strictures above 3 and exchanged every 2nd comparator One of right- Resection: sided hemihepatectomy, right trisegmentectomy, left hemihepatectomy, alone or hilar resection with transplantation, liver types of surgeryadditional Neoadjuvant when required. PDT and biliary drainage also if required given Treatment details Treatment yr 0.05). Further 0.05). < Treatment intention Treatment palliative Curative of cancer Type(s) and histology Hilar cholangiocarcinoma Main eligibility criteria Not stated characteristics Patient 52 % Male: 22–91 Age range: Patients from stage: Tumour IB and but mostly all stages, IIA Patients from extent: Tumour but mostly types, all Bismuth to both According type IV. and UICC Bismuth–Corlette were classifications there advanced tumours more treatment in the palliative than in the resection groups ( p group patient characteristics were reported of cases The number was confirmed histologically reported not clearly Concomitant treatment radiation Chemotherapy, chemoradiation therapy, and iridium implants were used occasionally Population details Population Non-RCT Full published Full Unclear – yr, which appears to which appears yr, 135 paper Country Germany English Language Study design of participants No. 184 (191 if including Total: patients not analysed seven due to missing FU data) 68 Intervention: 56 Comparator: 60 2nd Comparator: centres of recruiting No. Not stated period and Follow-up frequency recruited patients were 10 over be the FU period Study details source Data et al. Witzigmann et al. Authors (2006) UICC, International Union Against Cancer. International Union UICC, 277

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 19 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 A Authors’ conclusions PDT is minimally but there invasive is a considerable risk of cholangitis after the procedure. to PDT was found in a substantial result of prolongation survival time but need this would confirmation in further patient PDT has the series. in a potential to result of current changeover treatment palliative of BDC Brief study appraisal small trial with clear reporting of The procedures. to be appear results but would reliable need confirmation in a larger trial Interpretation QoL 0.01). In the PDT 0.01). = mth after a 2nd Not assessed wk after initial PDT, most wk after initial PDT, The PDT group had a longer The PDT group Three patients developed an infected an infected patients developed Three Mortality survival time compared to the endoprosthesis survival to the endoprosthesis time compared p (21 mth vs 7 mth, group group, 30-d mortality was 0% and 6% in the group, At the time of evaluation, group. endoprosthesis and one in patients in the PDT group three The still alive. were group the endoprosthesis deemed to be in good PDT patients were clinical condition without significant cholestasis. on the survivor in provided No details were In the PDT group group. the endoprosthesis causes, 12 patients died of tumour-related gastric ulcer. and one patient of a perforated the for not reported Causes of death were group endoprosthesis Morbidity 4 an almost complete PDT patients showed elimination of bile duct stenosis in the treated (data with cholangiography as shown area after 1st Median bilirubin level not provided). different intervention was not significantly the groups between to normal activity QoL and return the Karnofsky scale did not as assessed by after PDT improve significantly AEs cholangitis after bilioma with prolonged which could be managed PDT treatment, Another patient antibiotic treatment. by cholecystitis 2 developed which led to surgical session, treatment was no There cholecystectomy. laparoscopic of the observed in any skin phototoxicity severe One patient developed patients. three bacterial cholangitis during endoprosthetic by treated which was successfully therapy, antibiotic therapy standard use Resource Results µ m quartz mg/kg bw . In most cases . endoscopic 2 + J/cm s. the power density the power s. PDT W and a wavelength W and a wavelength mth and one patient a 3rd mth and one patient a 3rd mth or earlier in case of mth (1–9) after diagnosis of mW/cm and energy dose For J/cm of diffuser length. nm was used as light source. nm was used as light source. mth after the 2nd session. Further mth after the 2nd session. 3 ± hr before laser irradiation. A flexible laser irradiation. hr before this was around 550 this was around was 450–500 was 250–275 transpapillary was PDT the light applicator channel of the working inserted through PDT percutaneous For a duodenoscope. four patients the quartzwas guided in fibre percutaneous partiallyremoved the through the catheter and in one patient through channel of a cholangioscope. working at a The 1st PDT session was performed median of 4.5 a 2nd PDT Nine patients received BDC. session after 3–9 session 6 not reported. PDT parameters were with plastic provided All patients were after the PDT immediately endoprostheses treatment The aim of the Comparator hilar bilateral was treatment endoprosthetic regularly were Endoprostheses drainage. 3 changed every clotting or dislocation Treatment details Treatment Trial treatments treatments Trial drainage vs Endoscopic alone Intervention Photosan-3 was given at a dose of 2 intravenously 48 The was used. cylindrical diffuser probe was mounted on a 400- probe length of 4cm and a with an active fibre tip. at the distal fibre radiopaque marker A diode laser system with a maximum output of 2 power of 633 a light time was calculated for Irradiation energy density of 200 d All lymph lymph d. The d. g of + yr (range yr) min before intervention. intervention. min before Population details Population intention Treatment Palliative Main eligibility criteria BDC non-resectable Advanced, characteristics Patient 63 % Male: 68 Median age: 52–80 Stage II Cancer stage: nodes, one; stage IV, 31 stage IV, one; nodes, Initial median Karnofsky 90% status: performance (70–100) 63% of cases were Overall confirmed histologically Concomitant treatment prophylactic patients received before antibiotic treatment with 1 the procedure continuing but did not receive oral antibiotic treatment Ceftriaxon, given intravenously intravenously given Ceftriaxon, 30 antibiotic oral Ongoing with chinolone was treatment a total of 14 for given 1st eight PDT patients had 3 Cefriaxon over intravenous RCT 1, 3, 6, 9, 12 9, 6, 3, 1, mth. Earlier mth. Not stated 136 et al. Authors Zoepf et al. (2005) Study details Full Data source published paper Country Germany English Language Study design of participants No. 32 Total: 16 Intervention: 16 Comparator: of recruiting No. centres period and Follow-up frequency 3 and every endoscopic interventions when performed were needed in case of clotting or dislocation 278 279

Appendix 20 Brain cancer data extraction

278 279

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 20 ALA and Photofrin The Karnofsky Interpretation results were reported inconsistently within reported inconsistently were results difficult. making interpretation the paper, patients had many It was unclear how as 14 been randomised and treated, actually were biopsy results patients with negative The analyses. excluded from subsequently population does not therefore analysed the population presenting to reflect appear (patients with an MRI diagnosis). clinically Although the study made use of blinding it was nevertheless to assess outcomes, unclear whether suitable methods had been used to randomise and allocate participants reported were No results to treatments. The on possible photosensitisation effects. the need authors did though acknowledge larger study a much for Authors’ conclusions resection with fluorescence-guided a worthwhile survival PDT offer repetitive to patients risk, without added advantage, with GBM Brief study appraisal The 0.01) < d) mth had improved mth had improved wk in the surgery There was no difference was no difference There Mean survival in the PDT group 0.001) wk vs 24.2 < mth in the surgery ( p group Three patients had deep vein patients had deep vein Three Results Mortality was 52.8 ( p group There was no residual tumour was no residual There Morbidity on discharge scan in 10/13 PDT patients vs Mean time to tumour 4/14 surgery patients. was 8.6 mth in the PDT group progression vs 4.8 QoL and return to normal activity QoL and return at 6 Karnofsky score 70 (at baseline) to 80 in the PDT from an although the authors reported group, The scores of 20 points. improvement the surgery the same for group remained (at 70) AEs in the PDT of which were two thrombosis, occurred or seizures No infections group. use Resource in length of hospital the groups between of 7 (both had a mean stay stay nm) h mg/kg ALA orally ALA orally mg/kg Fluorescence-guided Fluorescence-guided nm) protoporphyrin-IX nm) protoporphyrin-IX hr. Patients also received Patients also received hr. ; more PDT was given at 72, at 72, PDT was given more ; 2 J/cm mW), was given in theatre recovery recovery in theatre was given mW), mg/kg Photofrin intravenously 48 mg/kg Photofrin intravenously of bulk After removal surgery. h before spectroscopy detection system was used spectroscopy tumour cells at remaining to detect any A size- removed. which were the margins, 10 balloon catheter was inflated to fit the After with 0.8% intralipid solution. cavity surgery from the 1st the patient awoke using 630-nm diode laser PDT treatment, (600 at 100 with a 440-nm observation filter was used with fluorescence to illuminate the cavity a high-quality photodiagnosis detected by and detected tumour was removed camera, until no furtherwas detected. fluorescence (405 A laser-based Treatment details Treatment treatments Trial PDT and and repetitive resection and resection vs standard radiotherapy radiotherapy given Patients were Intervention PDT: 2 and 20 surgery, before 3 of tumour violet-blue light (375–440 96, 120 and 144 96, on Advice was given radiotherapy. standard measures sun protection using removal Tumour Comparator and surgical the same neuronavigation Patients also as the PDT group. microscope radiotherapy standard received yr, yr, yr Some Curative 60 Population details Population Treatment intention of cancer Type(s) and histology GBM Main Eligibility Criteria 17 Patients over MRI with a new diagnosis of GBM and a Karnofsky score ≥ Patient characteristics 67 % Male: 59.8 Mean age: Mean Karnofsky score: performance 70 Concomitant treatment study patients additional received such treatments as chemotherapy and further surgery. there However, no statistically were significant differences the groups between in patients receiving treatments additional One 139 Study details Full Data source published paper Country UK English Language Study design RCT of No. participants 27 analysed Total: (42 randomised?) 13 Intervention: 14 Comparator: of recruiting No. centres Follow-up period Follow-up and frequency until 3-monthly, death Authors Eljamel et (2008) al. 280 imaging. magnetic resonance MRI, glioblastoma multiforme; GBM, DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Increasing Increasing This non- Authors’ conclusions of the odds the light dose increases deficit, permanent neurological having survivalbut does not increase time, There or time to tumour progression. with in recurrence was no difference light dose increasing Brief study appraisal to have randomised study appeared far too small a sample size to provide Results meaningful results. clinically all three for provided not always were groups Interpretation d in d in Not assessed 61). Group 1 not stated Group 61). = 106) in group 2 vs 238 106) in group Mean survival time was = Median Karnofsky rating Five patients had postoperative patients had postoperative Five d (sd Mortality 314 3 (sd group Morbidity 16 patients had in group after PDT (four recurrence 3), 2 and six in group six in group 1, Time to tumour did not. and two was a mean of 150 recurrence 1 Group 3. 2 vs 131d in group group not stated to normal QoL and return activity to 85 90 (pre-PDT) changed from (post PDT) AEs (zero defects permanent neurological and three 2, in group two 1, in group 3) in group use Resource Results J J J J nm) hr later mm) and PDT 1500–3700 J vs PDT 4400– J mg/kg, followed 24 followed mg/kg, wk by anaesthetic and CT or MRI by scan which locates tumour using Six optical system. arc stereotactic (1.6 diffusion tip fibres drill inserted central fibre through Red light (630 holes into skull. laser was pumped-dye an argon from and optical fibres through delivered beam splitters to individual diffusion biopsied were Tumours tip fibres. the (and if no malignancy was found the study). patient was excluded from advised about sunlight Patients were direct and about avoiding protection, sunlight and bright artificialfor light 6 Comparator PDT 3700–4400 See above 2): (group 2nd comparator PDT 4400–5900 See above 3): (group Treatment details Treatment vs PDT 3700–4400 5900 Intervention PDT 1500–3700 Photofrin Intravenous 1): (group at 2 Trial treatments treatments Trial Steroid Steroid Patients Curative Curative mth prior to 3 yr yr, with supratentorial yr, 60, and who had recurrent and who had recurrent 60, cm in diameter, a Karnofsky cm in diameter, 5 Population details Population Treatment intention Treatment Palliative of cancer and histology Type(s) anaplastic five 12 glioblastoma, one malignant astrocytoma, ependymoma Main eligibility criteria aged 18–75 primary malignant brain tumours ≤ rating ≥ eligible. tumours were or residual received Patients had to have > radiation therapy Further eligibility PDT treatment. reported criteria were characteristics Patient 32–70 Age range: 90 Median Karnofsky score: All locations also reported. Tumour radiation patients had initial surgery, before and chemotherapy therapy recurrence Concomitant treatment if required therapy One 138 wk, then at 3-mth wk, Study details Full Data source published paper Country USA English Language Study design Non-RCT of No. participants 18 Total: Six Intervention: Six Comparator: 2nd Comparator: Six of recruiting No. centres period Follow-up and frequency at 1 and 2, Days discharge from 4 and at 1, hospital, 6 intervals Authors et al. Krishnamurthy (2000) 281

283

Appendix 21 Head and neck cancer data extraction

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© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 21 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 PDT is effective PDT is effective This small pilot Interpretation Authors’ conclusions of advanced nasal the treatment for and safe pharyngeal cancer and the management of nasal obstruction Brief study appraisal no details on randomisation, study provided blinding and other study quality parameters raising questions about the validity of well details were Treatment the results. led on to have It does not appear described. though the authors rightly to a larger study, was needed stated that further investigation 0.04) PDT = 0.02). 0.02). wk later, wk later, = 0.001). No patients 0.001). = mth, 12 vs 2). In those 12 vs 2). mth, wk later d Not assessed All PDT related adverse effects and effects adverse All PDT related Results Mortality was clinical response Morbidity Overall better with PDT significantly statistically ( p than chemotherapy had more The PDT group CR. achieved response (i.e. patients with a significant 1 for 50% reduction patients with nasal obstructions PDT debulking ( p effective more produced vs 7/8 improved of 16 patients, (subgroup 2/8) to normal activity QoL and return significant greater had a statistically group ( p in Karnofsky score improvement 45 to 70 vs from increased PDT group 40 to from increased group chemotherapy 50 AEs to Treatment tolerable. were reactions the laryngopharynx in slight resulted area – secretion nasal cavity pain and increased in 3–5 resolved laryngopharynx swelling One case of severe 1 with treatment Resolved and pain. to light exposure be related may One case of photosensitivity dermatitis after Resolved to daylight. accidental exposure 1 after treatment, no treatment One case of skin pigmentation, required cm) and 5-FU 2 mg/m J/cm from a diode J/cm from PDT vs Chemotherapy PDT vs Chemotherapy , both divided into five. Each cycle both divided into five. , nm) at 200–300 2 wk. Two cycles were given cycles were Two wk. wk after treatment. Maximum Maximum wk after treatment. mg/m hr after injection. Light was applied to Light was applied hr after injection. Segments had at least a min per segment. mg/kg. Local anaesthetic (lidocaine) before Local anaesthetic (lidocaine) before mg/kg. Treatment details Treatment treatments Trial (cisplatin and 5-FU) Photofrin of Intervention Intravenous 2 light (630 laser through a cylindrical diffuser (1–5 laser through 48 segments for overlapping one to three 12 After 48-hr the lesion. 0.5-cm margin beyond biopsy forceps by tissue removed necrotic re-treated exposed lesions were and newly when Cleaning was repeated after cleaning. sunlight to avoid Patients asked necessary. 4–6 for number of sessions was not stated number Comparator Cisplatin 80 500 lasted 4 yr Anti- Not stated, Not stated, mth before trial mth before Population details Population Treatment intention palliative appears of cancer Type(s) and histology Nasopharyngeal carcinoma Main eligibility criteria Patients who had relapsed and who had failed radiotherapy Patient characteristics 80 % Male: 28–72 Age range: 54 Mean age: All Cancer stage: stage IV and had local All had prior relapse. (failed) radiotherapy; some also had prior chemotherapy, 6–12 treatment Concomitant treatment treatment vomiting chemotherapy for Chinese herbs group. (unspecified) FU Not 141 Authors Li et (2006) al. Study details Data source Full published paper Country China Language English Study design RCT of No. participants 30 Total: 15 Intervention: 15 Comparator: of No. recruiting centres 3 and 6 at 1, mth 284 stated Follow-up period and frequency 285

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 21 DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 This study Interpretation Authors’ conclusions PDT in patients Intraoperative laryngealII and I stages with cancer preventing for could be effective and metastasis of recurrence tumours Brief study appraisal such used comparator treatments little insight offer that the results to other PDT compares to how to surgery. adjunctive treatments The study also examined few was sparse outcomes and there patient reporting of methods, characteristics and results yr there was yr there Not assessed PDT group: Some patients PDT group: Results recurrence in one patient (2%) and recurrence no cases of metastasis in the PDT cases of recurrence four group, and one (8%) in the laser group cases and five case of metastasis, cases (10%) and two of recurrence of metastasis in the Surgery-alone group to normal QoL and return activity AEs had oedema of laryngeal mucous membrane and one patient had a Surgery-alone small haemorrhage. One patient had a small group: Both haemorrhages haemorrhage. conservative managed by were treatment After 3 Morbidity

2 mW/cm Surgery/ min was used. Further PDT min was used. nm emitting at 25–30 Trial treatments treatments Trial PDT vs Surgery/intraoperative PDT without laser intraoperative vs Surgery alone with Intervention Cordectomy by followed local anaesthetic, administration of 0.4% solution blue photosensitiser. methylene A He-Ne laser of wavelength 633 Treatment details Treatment for 5 for not reported parameters were with Comparator Cordectomy laser by local anaesthetic followed (same parameters as PDT only group) 2nd comparator Cordectomy with local anaesthetic only Not Not Cancer Curative stated Type(s) of Cancer and Type(s) Histology Planocellular cancer of larynx Main eligibility criteria All 66. stage IIa, 79; Stage Ib, stage: localisation. middle of were cancers No further characteristics were reported Concomitant treatment Treatment intention Treatment stated characteristics Patient Population details Population Non-RCT yr 3 142 et al. Authors Loukatch et al. (1995) 284 Study details Abstract Data source Country Ukraine English Language Study design of participants No. 145 Total: 42 Intervention: 51 Comparator: 52 2nd Comparator: centres of recruiting No. Not stated period and Follow-up frequency 285

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 21 PDT appears PDT appears This study used Authors’ conclusions tumours of the pharynx, in treating effective needed but larger studies with longer FU are Brief study appraisal such that the results comparator treatments with PDT compares little insight to how offer There to surgery. adjunctive other treatments of methods and patient was sparse reporting sometimes were and results characteristics, incomplete Interpretation Not assessed d) No complications postoperatively, except some No complications postoperatively, Mortality 2-yr survival 89% (stages III and IV); 100% (stage II), PDT group, 86% (stages III and 88% (stage II), group: Laser-only 75% 71% (stage II), group: Photosensitiser-only IV); (stages III and IV) 3-yr survival 67% (stages III and 100% (stage II), PDT group, 43% (stages III and IV); group: Laser-only IV); 38% (stages III and IV). group: Photosensitiser-only groups last two for not available Stage II results none of the stage II patients After 1 year, Morbidity stage III and For or metastasis. had recurrence in one patient was recurrence there IV patients, patients (29%) in the two (11%) in the PDT group, patients (25%) in the and two group Laser-only group Photosensitiser-only in 10% (stage recurrence in the PDT group: After 2 yr, group: in the Laser-only II) and 11% (stages III IV); and 43% (stages III in 25% (stage II), recurrence in recurrence group: in the Photosensitiser-only IV); and 50% (stages III IV) 43% (stage II), regional were During the 3-yr period there 11% in (stage II), metastases in 0% of PDT group group 13% of Laser-only PDT (stages III and IV), 14% (stages III and IV), 14% Laser-only (stage II), 25% Photosensitiser- (stage II), Photosensitiser-only (stages III and IV) only to normal activity QoL and return AEs patients had minor oedema of the pharyngeal mucous within 5 membrane (resolved Results PDT vs . Further . 2 mW/cm min from a He-Ne laser min from PDT parameters were not PDT parameters were reported As for Comparator but without PDT group photosensitiser 2nd comparator As for but without laser PDT group Treatment details Treatment treatments Trial PDT with Laser only vs PDT PDT with Laser only with Photosensitiser only Intervention PDT with blue (injected methylene as photosensitiser, locally) 633-nm light for by followed 5 at 25–30

Pharyngotomy Pharyngotomy Population details Population intention Treatment Curative of cancer Type(s) and histology SCC in laryngeal part of pharynx Main eligibility criteria Not stated characteristics Patient 25; Stage II, Cancer stage: 24 stages III and IV, No further characteristics reported were Concomitant treatment stage II patients and for hemilaryngopharyngotomy stage III–IV patients for with general anaesthetic. cobalt Postoperative (45-Gy dose). therapy Neck dissection operation patients developing for metastases yr 3 Not 143 Authors Loukatch et al. (1996) 286 Study details Data source Abstract Country Ukraine Language English Study design Non-RCT of No. participants 49 Total: 19 Intervention: 15 Comparator: 2nd 15 Comparator: of No. recruiting centres stated Follow-up period and frequency DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Our Minimal Interpretation reporting of both methods and results reporting of both methods and results this means little can be deduced from abstract conference Authors’ conclusions pronounced experience showed efficacy of PDT with high functional oral cancer of for and cosmetic effects localisations different Brief study appraisal

Not broken down by by down Not broken Main side effect with Photosense Main side effect Results Mortality group treatment Photosense a CR was Morbidity For seen in 57% of patients and a PR Radachlorin a CR was seen in For 38%. 20% and a PR in 50% to normal activity QoL and return Not assessed AEs skin sensitivity to was increased with Radachlorin skin sunlight, direct No further sensitivity is short term. given details were . . . 2 2 J/cm J/cm PDT with mg/kg) with semiconductive mg/kg) with semiconductive mg/kg) with semiconductive mg/kg) with semiconductive Treatment details Treatment Further PDT parameters were not Further PDT parameters were reported Radachlorin Comparator Intravenous (1.2–2.4 Biospec 672) at lasers (Milon 660, a total light dose of 200–300 not Further PDT parameters were reported Trial treatments treatments Trial Photosense vs PDT with Radachlorin Photosense Intervention Intravenous (0.4–0.8 Biospec 672) at lasers (Milon 660, a total light dose of 400–600 Patients Not stated Population details Population Treatment intention Treatment Not stated of cancer and Type(s) histology Oral cancer (SCC) Main eligibility criteria Not stated Patient characteristics had tumours in the oral oropharynx or cavity, Further patient lip. lower not characteristics were reported Concomitant treatment 213 Non-RCT Not stated yr) 144 Vakulovskaya Authors (2007) Study details publications Linked Abstract Data source Country Russia English Language Study design No. of participants No. 52 Total: Not stated Intervention: Not stated Comparator: centres of recruiting No. Not stated period and Follow-up frequency (although survival monitored up to 3 287

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