Letters to the Editor critical appraisal of the Multicenter Selective Lymphadenectomy Trial-I final report. Br J Dermatol 2015; 172:566–71. 5 Smyth R, Kirkham JJ, Jacoby A et al. Frequency and reasons for outcome reporting bias in clinical trials: interviews with trialists. BMJ 2011; 342:c7153.
The choice and measurement of fluence in photodynamic therapy for superficial basal cell carcinoma DOI: 10.1111/bjd.14020 DEAR EDITOR, We read with interest the article by Roozeboom et al.1 on the comparison of imiquimod 5% and methyl aminolaevulinate photodynamic therapy (PDT) using a light dose of 375 J cm 2 of 636-nm light for the treatment of superficial basal cell carcinoma (BCC). The data used were acquired during a study comparing the mentioned low-fluence PDT, imiquimod 5% and fluorouracil 5% on which those authors had previously reported.2 There are some peculiarities that suggest that the study suffered from a bias in favour of the applied pharmacotherapy. This follows from the rather low optical fluence used for PDT in the study. To understand the relevance, one needs to take into account the effect that the optical fluence has on the efficacy of PDT. As was suggested in one of the seminal publications on PDT of BCCs using topical 5-aminolaevulinic acid and red light, it has been shown that the depth at which PDT has an effect depends directly on the applied fluence.3,4 Low amounts of fluence such as 375 J cm 2 are generally insufficient to achieve the required photodynamic damage for BCC tumour destruction at all but the most superficial regions of the epidermis. In that sense the results reported by the authors are actually better than expected. Following these insights, the recommended dose is 75– 150 J cm 2.5 Protocols such as the fractioned PDT from Rotterdam apply a total dose of 100 J cm 2 of 636-nm light. Unsurprisingly, these treatments result in higher clearance rates.6,7 The problem of low fluence is further compounded by other decisions by the authors. The treated areas were covered following PDT, thereby preventing any additional irradiation after treatment. Such additional illumination might have alleviated the low-fluence problem in some patients, most notably when treating lesions on the face. In patients with multiple superficial BCCs, the authors did not opt to apply a random method of selection, but rather included the largest lesions. Larger lesions are quite likely to be thicker lesions requiring more energy. This again strengthened the low-fluence bias. A couple of observations from the publications support our conjecture. Firstly, the authors note that larger lesions respond less to PDT, which can more appropriately be explained by the insufficient fluence. PDT is able to detect and treat preclinical lesions,8 and the difference in scattering does not explain
© 2015 British Association of Dermatologists
1105
the observations.9 Secondly, the authors report unexpectedly positive results for PDT on the arms and legs. As the distance from the light source to the skin was not standardized, it allowed for the possibility that the light source was mounted closer to the target when treating an arm or a leg. As a result, the actual fluence on the skin would have been multiplied. As the main determinant of pain in PDT is irradiance,10 it would be interesting to see whether treatment on the arms or legs was more often associated with severe pain. Aside from using the appropriate fluence, this problem could have been prevented with a limited amount of effort and resources. Photobleaching is a well-established method to measure photodynamic damage in PDT.5 Had the authors applied this technique as a measure during treatment, the low-fluence bias would have been avoided as the illumination would have been tailored to the lesion. Any discussion on the variation in fluence from a difference in the distance between target and light source could have been avoided either by standardizing the distance and angle of incidence of the light source, or preferably by measuring the irradiance on the skin. Given that therefore there is some uncertainty in the results due to this unintended bias, we recommend that a replacement study uses the fractionated PDT protocol mentioned above, and in addition applies a standardized procedure for the positioning of the light source, as well as a verification of the induced photodynamic damage using a validated fluorescence detection system. We conclude that, based on the study design in combination with the evaluation of the reported results, when compared with the current scientific knowledge, there are very good reasons to believe that the outcome of this study was to a substantial degree influenced by an unintended bias. As a consequence, we caution against the use of the results of the original study in guidelines and other policy-related documents. 1
ZBC Multicare, Independent Treatment Centre for Dermatology, Hilversum, the Netherlands 2 Erasmus Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands 3 School of Applied Computing, University of Wales Trinity St David, Swansea, U.K. 4 Institute of Life Science, Swansea University, Swansea, U.K. 5 Mølholm Private Hospital, Vejle, Denmark E-mail: [email protected]
N.
VAN DER
BEEK1,2,3
P. BJERRING1,4,5 H.A.M. NEUMANN1,2
References 1 Roozeboom MH, Nelemans PJ, Mosterd K et al. Photodynamic therapy vs. topical imiquimod for treatment of superficial basal cell carcinoma: a subgroup analysis within a noninferiority randomized controlled trial. Br J Dermatol 2015; 172:739–45. 2 Arits AHMM, Mosterd K, Essers BA et al. Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of
British Journal of Dermatology (2015) 173, pp1095–1111
1106 Letters to the Editor
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4
5
6
7
8
9
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superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial. Lancet Oncol 2013; 14:647–54. Valentine RM, Ibbotson SH, Wood K et al. Modelling fluorescence in clinical photodynamic therapy. Photochem Photobiol Sci 2013; 12:203–13. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol, B 1990; 6:143–8. Valentine RM, Ibbotson SH, Brown CTA et al. A quantitative comparison of 5-aminolaevulinic acid- and methyl aminolevulinate-induced fluorescence, photobleaching and pain during photodynamic therapy. Photochem Photobiol 2011; 87:242–9. De Vijlder HC, Sterenborg HJCM, Neumann HAM et al. Light fractionation significantly improves the response of superficial basal cell carcinoma to aminolaevulinic acid photodynamic therapy: five-year follow-up of a randomized, prospective trial. Acta Derm Venereol 2012; 92:641–7. De Haas ERM, Kruijt B, Sterenborg HJCM et al. Fractionated illumination significantly improves the response of superficial basal cell carcinoma to aminolevulinic acid photodynamic therapy. J Invest Dermatol 2006; 126:2679–86. De Leeuw J, van der Beek N, Neugebauer WD et al. Fluorescence detection and diagnosis of non-melanoma skin cancer at an early stage. Lasers Surg Med 2009; 41:96–103. Salomatina E, Jiang B, Novak J, Yaroslavsky AN. Optical properties of normal and cancerous human skin in the visible and near-infrared spectral range. J Biomed Opt 2006; 11:064026. Cottrell WJ, Paquette AD, Keymel KR et al. Irradiance-dependent photobleaching and pain in delta-aminolevulinic acid-photodynamic therapy of superficial basal cell carcinomas. Clin Cancer Res 2008; 14:4475–83.
Funding sources: none. Conflicts of interest: P.B. acts as a consultant to Galderma.
The choice and measurement of fluence in photodynamic therapy for superficial basal cell carcinoma: reply from the authors DOI: 10.1111/bjd.14029 DEAR EDITOR, We would like to thank van der Beek and coworkers for their interest1 in our recently published article.2 We are pleased to have the opportunity to respond to their comments. As stated in the methods section of our article, superficial basal cell carcinomas (sBCCs) were illuminated with a light dose of 375 J cm 2 per treatment, and treatment was repeated after 1 week. Consequently, the required total light dose of 75 J cm 2 was obtained according to the methyl aminolaevulinate photodynamic therapy (MAL-PDT) protocol (Metvixâ; Galderma, Lausanne, Switzerland). The protocol was verified and approved by experts of Galderma prior to the start of the study. Within this PDT protocol, it is stated that the treated area should be covered with an occlusive dressing after illumination, and the light source should be positioned in a standardized matter. We strictly applied this protocol in all treated sBCCs. British Journal of Dermatology (2015) 173, pp1095–1111
van der Beek et al. noted that in patients with multiple BCCs, the most accessible sBCC for treatment and the largest tumour were included. They suspected these lesions to be thicker than others and thus they would require more energy. Firstly, we would like to mention that only 14% (28 of 196) of patients treated with MAL-PDT had more than one BCC. In addition, the median tumour size in the MAL-PDT group was not large (52 mm2) and was even smaller than in the imiquimod group (63 mm2).2 We analysed the histological data from the same noninferiority randomized controlled trial to investigate the effect of sBCC treatment failure with MAL-PDT, imiquimod and 5-fluorouracil.3,4 The results showed that the maximum tumour thickness of the included sBCC was 10 mm, and was not significantly associated with treatment failure after one of the three noninvasive therapies. Furthermore, van der Beek et al. mentioned that unexpected positive results were found for tumours on the arms and legs. They wanted to know whether treatment on these area was more often associated with pain. Firstly, we want to mention that a higher probability of treatment success for MAL-PDT was found in elderly patients with a sBCC only on the lower extremities, not on the upper extremities (arms). Severe pain was most often seen in tumours localized in the head and neck region (19%), followed by the lower extremities (15%), trunk (6%) and upper extremities (3%). This corroborates previous findings that pain during PDT treatment is unpredictable but occurs most often in the head and neck region.5 We are aware of the fact that other protocols are being investigated. However, we have chosen to compare the most used protocol worldwide in this trial.6 We agree with our colleagues that further research is necessary to demonstrate that other treatment protocols might result in a better outcome. In conclusion, the effectiveness of MAL-PDT was carefully studied in a large randomized controlled trial by using the internationally accepted MAL-PDT protocol. We therefore adhere to our previous recommendation that imiquimod should remain the treatment of first choice in most patients with sBCC. However, MAL-PDT must be considered in the subgroup of elderly patients with sBCC on the legs. M.H. ROOZEBOOM Department of Dermatology, Maastricht University Medical Centre, P. Debyelaan 25, A.H.M.M. ARITS 6229 HX Maastricht, the Netherlands N.W.J. KELLENERS-SMEETS E-mail: [email protected]
References 1 van der Beek N, Bjerring P, Neumann HAM. The choice and measurement of fluence in photodynamic therapy for superficial basal cell carcinoma. Br J Dermatol 2015; 173:1105–6. 2 Roozeboom MH, Nelemans PJ, Mosterd K et al. Photodynamic therapy vs. topical imiquimod for treatment of superficial basal cell carcinoma: a subgroup analysis within a noninferiority randomized controlled trial. Br J Dermatol 2015; 172:739–45. 3 Arits AHMM, Mosterd K, Essers BA et al. Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of © 2015 British Association of Dermatologists
The choice and measurement of fluence in photodynamic therapy for superficial basal cell carcinoma DOI: 10.1111/bjd.14020 DEAR EDITOR, We read with interest the article by Roozeboom et al.1 on the comparison of imiquimod 5% and methyl aminolaevulinate photodynamic therapy (PDT) using a light dose of 375 J cm 2 of 636-nm light for the treatment of superficial basal cell carcinoma (BCC). The data used were acquired during a study comparing the mentioned low-fluence PDT, imiquimod 5% and fluorouracil 5% on which those authors had previously reported.2 There are some peculiarities that suggest that the study suffered from a bias in favour of the applied pharmacotherapy. This follows from the rather low optical fluence used for PDT in the study. To understand the relevance, one needs to take into account the effect that the optical fluence has on the efficacy of PDT. As was suggested in one of the seminal publications on PDT of BCCs using topical 5-aminolaevulinic acid and red light, it has been shown that the depth at which PDT has an effect depends directly on the applied fluence.3,4 Low amounts of fluence such as 375 J cm 2 are generally insufficient to achieve the required photodynamic damage for BCC tumour destruction at all but the most superficial regions of the epidermis. In that sense the results reported by the authors are actually better than expected. Following these insights, the recommended dose is 75– 150 J cm 2.5 Protocols such as the fractioned PDT from Rotterdam apply a total dose of 100 J cm 2 of 636-nm light. Unsurprisingly, these treatments result in higher clearance rates.6,7 The problem of low fluence is further compounded by other decisions by the authors. The treated areas were covered following PDT, thereby preventing any additional irradiation after treatment. Such additional illumination might have alleviated the low-fluence problem in some patients, most notably when treating lesions on the face. In patients with multiple superficial BCCs, the authors did not opt to apply a random method of selection, but rather included the largest lesions. Larger lesions are quite likely to be thicker lesions requiring more energy. This again strengthened the low-fluence bias. A couple of observations from the publications support our conjecture. Firstly, the authors note that larger lesions respond less to PDT, which can more appropriately be explained by the insufficient fluence. PDT is able to detect and treat preclinical lesions,8 and the difference in scattering does not explain
© 2015 British Association of Dermatologists
1105
the observations.9 Secondly, the authors report unexpectedly positive results for PDT on the arms and legs. As the distance from the light source to the skin was not standardized, it allowed for the possibility that the light source was mounted closer to the target when treating an arm or a leg. As a result, the actual fluence on the skin would have been multiplied. As the main determinant of pain in PDT is irradiance,10 it would be interesting to see whether treatment on the arms or legs was more often associated with severe pain. Aside from using the appropriate fluence, this problem could have been prevented with a limited amount of effort and resources. Photobleaching is a well-established method to measure photodynamic damage in PDT.5 Had the authors applied this technique as a measure during treatment, the low-fluence bias would have been avoided as the illumination would have been tailored to the lesion. Any discussion on the variation in fluence from a difference in the distance between target and light source could have been avoided either by standardizing the distance and angle of incidence of the light source, or preferably by measuring the irradiance on the skin. Given that therefore there is some uncertainty in the results due to this unintended bias, we recommend that a replacement study uses the fractionated PDT protocol mentioned above, and in addition applies a standardized procedure for the positioning of the light source, as well as a verification of the induced photodynamic damage using a validated fluorescence detection system. We conclude that, based on the study design in combination with the evaluation of the reported results, when compared with the current scientific knowledge, there are very good reasons to believe that the outcome of this study was to a substantial degree influenced by an unintended bias. As a consequence, we caution against the use of the results of the original study in guidelines and other policy-related documents. 1
ZBC Multicare, Independent Treatment Centre for Dermatology, Hilversum, the Netherlands 2 Erasmus Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands 3 School of Applied Computing, University of Wales Trinity St David, Swansea, U.K. 4 Institute of Life Science, Swansea University, Swansea, U.K. 5 Mølholm Private Hospital, Vejle, Denmark E-mail: [email protected]
N.
VAN DER
BEEK1,2,3
P. BJERRING1,4,5 H.A.M. NEUMANN1,2
References 1 Roozeboom MH, Nelemans PJ, Mosterd K et al. Photodynamic therapy vs. topical imiquimod for treatment of superficial basal cell carcinoma: a subgroup analysis within a noninferiority randomized controlled trial. Br J Dermatol 2015; 172:739–45. 2 Arits AHMM, Mosterd K, Essers BA et al. Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of
British Journal of Dermatology (2015) 173, pp1095–1111
1106 Letters to the Editor
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4
5
6
7
8
9
10
superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial. Lancet Oncol 2013; 14:647–54. Valentine RM, Ibbotson SH, Wood K et al. Modelling fluorescence in clinical photodynamic therapy. Photochem Photobiol Sci 2013; 12:203–13. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol, B 1990; 6:143–8. Valentine RM, Ibbotson SH, Brown CTA et al. A quantitative comparison of 5-aminolaevulinic acid- and methyl aminolevulinate-induced fluorescence, photobleaching and pain during photodynamic therapy. Photochem Photobiol 2011; 87:242–9. De Vijlder HC, Sterenborg HJCM, Neumann HAM et al. Light fractionation significantly improves the response of superficial basal cell carcinoma to aminolaevulinic acid photodynamic therapy: five-year follow-up of a randomized, prospective trial. Acta Derm Venereol 2012; 92:641–7. De Haas ERM, Kruijt B, Sterenborg HJCM et al. Fractionated illumination significantly improves the response of superficial basal cell carcinoma to aminolevulinic acid photodynamic therapy. J Invest Dermatol 2006; 126:2679–86. De Leeuw J, van der Beek N, Neugebauer WD et al. Fluorescence detection and diagnosis of non-melanoma skin cancer at an early stage. Lasers Surg Med 2009; 41:96–103. Salomatina E, Jiang B, Novak J, Yaroslavsky AN. Optical properties of normal and cancerous human skin in the visible and near-infrared spectral range. J Biomed Opt 2006; 11:064026. Cottrell WJ, Paquette AD, Keymel KR et al. Irradiance-dependent photobleaching and pain in delta-aminolevulinic acid-photodynamic therapy of superficial basal cell carcinomas. Clin Cancer Res 2008; 14:4475–83.
Funding sources: none. Conflicts of interest: P.B. acts as a consultant to Galderma.
The choice and measurement of fluence in photodynamic therapy for superficial basal cell carcinoma: reply from the authors DOI: 10.1111/bjd.14029 DEAR EDITOR, We would like to thank van der Beek and coworkers for their interest1 in our recently published article.2 We are pleased to have the opportunity to respond to their comments. As stated in the methods section of our article, superficial basal cell carcinomas (sBCCs) were illuminated with a light dose of 375 J cm 2 per treatment, and treatment was repeated after 1 week. Consequently, the required total light dose of 75 J cm 2 was obtained according to the methyl aminolaevulinate photodynamic therapy (MAL-PDT) protocol (Metvixâ; Galderma, Lausanne, Switzerland). The protocol was verified and approved by experts of Galderma prior to the start of the study. Within this PDT protocol, it is stated that the treated area should be covered with an occlusive dressing after illumination, and the light source should be positioned in a standardized matter. We strictly applied this protocol in all treated sBCCs. British Journal of Dermatology (2015) 173, pp1095–1111
van der Beek et al. noted that in patients with multiple BCCs, the most accessible sBCC for treatment and the largest tumour were included. They suspected these lesions to be thicker than others and thus they would require more energy. Firstly, we would like to mention that only 14% (28 of 196) of patients treated with MAL-PDT had more than one BCC. In addition, the median tumour size in the MAL-PDT group was not large (52 mm2) and was even smaller than in the imiquimod group (63 mm2).2 We analysed the histological data from the same noninferiority randomized controlled trial to investigate the effect of sBCC treatment failure with MAL-PDT, imiquimod and 5-fluorouracil.3,4 The results showed that the maximum tumour thickness of the included sBCC was 10 mm, and was not significantly associated with treatment failure after one of the three noninvasive therapies. Furthermore, van der Beek et al. mentioned that unexpected positive results were found for tumours on the arms and legs. They wanted to know whether treatment on these area was more often associated with pain. Firstly, we want to mention that a higher probability of treatment success for MAL-PDT was found in elderly patients with a sBCC only on the lower extremities, not on the upper extremities (arms). Severe pain was most often seen in tumours localized in the head and neck region (19%), followed by the lower extremities (15%), trunk (6%) and upper extremities (3%). This corroborates previous findings that pain during PDT treatment is unpredictable but occurs most often in the head and neck region.5 We are aware of the fact that other protocols are being investigated. However, we have chosen to compare the most used protocol worldwide in this trial.6 We agree with our colleagues that further research is necessary to demonstrate that other treatment protocols might result in a better outcome. In conclusion, the effectiveness of MAL-PDT was carefully studied in a large randomized controlled trial by using the internationally accepted MAL-PDT protocol. We therefore adhere to our previous recommendation that imiquimod should remain the treatment of first choice in most patients with sBCC. However, MAL-PDT must be considered in the subgroup of elderly patients with sBCC on the legs. M.H. ROOZEBOOM Department of Dermatology, Maastricht University Medical Centre, P. Debyelaan 25, A.H.M.M. ARITS 6229 HX Maastricht, the Netherlands N.W.J. KELLENERS-SMEETS E-mail: [email protected]
References 1 van der Beek N, Bjerring P, Neumann HAM. The choice and measurement of fluence in photodynamic therapy for superficial basal cell carcinoma. Br J Dermatol 2015; 173:1105–6. 2 Roozeboom MH, Nelemans PJ, Mosterd K et al. Photodynamic therapy vs. topical imiquimod for treatment of superficial basal cell carcinoma: a subgroup analysis within a noninferiority randomized controlled trial. Br J Dermatol 2015; 172:739–45. 3 Arits AHMM, Mosterd K, Essers BA et al. Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of © 2015 British Association of Dermatologists
