A Randomized Assessor-blinded Comparison of Low Irradiance and Conventional Irradiance Photodynamic Therapy (PDT) for Superficial Non-melanoma Skin Cancer
Phase: NA
Conditions: Non-melanoma Skin Cancer
Sponsor: Sally Ibbotson

ambvconv/jg/v.4                                                                                                           02/05/2012 
 
                        
          
 
                                                                               
                          
A randomised assessor-blinded comparison of low 
irradiance and conventional irradiance photodynamic 
therapy for superficial non-melanoma skin cancer 
 
Protocol 
 
 
      Chief Investigator:   
 
       Investigators:   
 
       
       
 
Introduction 
Skin cancer is the commonest malignancy in Caucasians and is a major cause of morbidity and 
burden on health services1.  Patients with superficial non-melanoma skin cancer (NMSC) are 
frequently elderly and frail and surgery is often not appropriate or feasible and non–surgical 
approaches, such as topical photodynamic therapy (PDT), are ideally suited to treat these 
lesions.  Topical PDT has been increasingly used to non-invasively treat superficial NMSC and 
dysplasia since its introduction in 1990 and this now has National and European Guidelines for 
use and NICE technology (http://guidance.nice.org.uk/IPG155) and Scottish Medicines 
Consortium approval (Methyl aminolevulinate (Metvix cream) - SMC approval for AK (50/03) 
and BCC (51/03) November 2003 http://www.scottishmedicines.org.uk)2-4.  
 
At present PDT is hospital-based and requires the patient to come up as a day case, wait for 3 - 
6 hours (depending on the treatment regime), while the cream is in place and conversion to the 
photosensitiser occurs, before irradiation takes place over a further 15 - 20 minutes.  
Essentially, patients are at the hospital for most of the day.  Treatment is repeated at one week, 
and these two treatments one week apart constitute a treatment cycle.  

ambvconv/jg/v.4                                                                                                           02/05/2012 
 
 
Subsequently, at three month follow-up, if complete resolution of the lesion is not apparent then 
a second treatment cycle is undertaken.  Thus, this will require the patient to attend for four day 
case procedures, which is tiring and time consuming for elderly, frail patients and, because of 
the time involved, limits the number of patients that can be treated in one session at the 
hospital.  Thus, there is a major demand for treatment to be more efficient and patient-
orientated.   
 
Furthermore, during the irradiation of PDT significant pain is experienced by most patients. In 
our Unit, 16% of PDT treatments (n=4717) were associated with severe pain.  The mechanism 
of PDT-induced pain is not well understood and conventional methods of pain relief, such as 
topical anaesthetics are not very effective5-7.  This can limit successful delivery of PDT and 
negatively impact on the patient’s experience of treatment.   
 
Low irradiance irradiation enhances photobleaching efficiency and the PDT effect when 
compared with higher irradiance light delivery, as oxygen depletion is less rapid when irradiation 
occurs over a longer time period8, reviewed in 9).  Furthermore, there is preliminary evidence that 
low irradiance PDT is less painful than conventional PDT, and indeed if this is the case, then 
this would significantly improve the patient’s experience of PDT and successful delivery and 
wide acceptance of this therapy10,11.  We will translate these findings into clinical practice by 
investigating low irradiance ambulatory PDT in the proposed clinical trial. 
 
 
Results of pilot studies   
A novel CE-marked portable red light LED source has been developed in the form of a “skin 
cancer plaster” (Ambulight, Ambicare Health).  This is able to deliver a standard PDT light dose 
at very low irradiance over a prolonged time period.  Thus, the Ambulight delivers light at low 
irradiance (7 mW/cm2 as compared to 80-90 mW/cm2 with conventional PDT), such that the 
total dose (75 J/cm2) is delivered over 3 hours as compared to approximately 15 - 20 minutes 
for conventional hospital-based devices.  The light source is small, light and compact and 
attached to a battery pack, such that patients can put the battery pack in a pocket and be mobile 
during treatment.  This has been established in clinical practice in order for patients to receive 
treatment at home. 
 
 
Initial studies of prototype devices in small numbers of patients showed that it could be 
successfully used for low irradiance topical PDT, and preliminary data suggested that treatment 
was less painful and of similar efficacy to conventional PDT9,12.  Subsequently, the more 
portable and compact Ambulight device was developed and our preliminary clinical data using 
this in eight patients with multiple lesions of NMSC who were treated simultaneously with both 
conventional PDT and low irradiance Ambulight PDT showed a significant difference in pain 
experienced, with the VAS score for pain of conventional PDT being 5.2 (2 - 9) cm compared 
with 1.5 (0 – 3) cm for low irradiance Ambulight PDT (values given as median (range), p<0.05).   
 
Study aims 
The primary aim of this study is to examine whether the pain and discomfort of topical PDT is 
significantly different when using the low irradiance ambulatory LED device compared with 
conventional higher irradiance PDT and this is the first randomised controlled trial in this 
important clinical area.  We will also examine possible differences in phototoxicity of the two 

ambvconv/jg/v.4                                                                                                           02/05/2012 
 
regimes and assess patient evaluation of treatment.  The secondary end-point of efficacy of the 
two treatment regimes will be examined. 
 
Research Questions 
1. Is there a significant difference in pain and phototoxicity experienced with low irradiance 
ambulatory PDT compared with conventional higher irradiance PDT? 
2. Is there a large difference in efficacy of treatments at one year follow-up?  
3. Do patients prefer ambulatory or conventional PDT? 
 
Clinical trial study design 
 a prospective, randomised, controlled, single-blind, comparison of low irradiance ambulatory 
MAL-PDT with conventional higher irradiance MAL PDT for patients with superficial NMSC.  
 
Participants 
Study details would be disseminated to local dermatology colleagues and plastic surgeons, as 
these are the sources of referral to the PDT Clinic in the Photobiology Unit.  The PI will screen 
all referral letters for PDT and any patient with superficial basal cell carcinoma or Bowen’s 
disease (diameter =/< 2 cm) will be sent out a Participant Information Sheet (PIS).  They will be 
invited to participate in the study when they attend the PDT clinic.  Exclusion criteria will be 
patients with lesions >2 cm diameter, patients unable to give consent, patients with lesions at 
sites where the portable device would be difficult to apply such as highly curved sites e.g. rim of 
ear.  The aim will be to recruit 50 patients and they will be randomised to receive either low 
irradiance ambulatory PDT or conventional higher irradiance PDT.  After obtaining written 
consent, demographic details and assessment of the lesion will be undertaken and the area will 
be mapped and photographed.   
 
Randomisation 
A blocked randomisation list will be computer generated. Randomisation codes will be 
concealed in opaque sealed envelopes and will only be opened at the time of entry of the 
patient to the study and this will be carried out by the Photobiology Technician.  Patients will 
then receive their randomised treatment and this will also be undertaken by the Photobiology 
Technician as is the normal clinical practice in the PDT Unit.   
 
 
 
Interventions 
The study outline is shown in Appendix 1.   
 
Treatment allocations will be:  
Conventional PDT: Lesions will be gently scraped using a disposable ring curette (Stiefel®) and 
MAL cream (16% w/v, Galdema UK) will be applied to the lesion and occluded under 
Tegaderm® and Mepore® for three hours.  Dressings and residual cream will then be carefully 
removed and irradiation of the lesion, including a 5 mm rim of clinically normal-appearing tissue, 
will be undertaken.  Irradiation will be performed using the Aktilite 128/16 device (peak 
wavelength 636 nm, full width half maximum (FWHM) 18 nm) to deliver a total dose of 75 J/cm2.  
Immediately after irradiation a dressing will be applied and the patient will go home. 
 
Low irradiance ambulatory PDT: The lesion will be prepared and MAL cream applied as above.  
Immediately after cream application, the Ambulight device will be applied and will adhere to the 

ambvconv/jg/v.4                                                                                                           02/05/2012 
 
treatment site.  This is automated to be in place and switched off for three hours and will then 
switch on and irradiate the lesion for a further three hours to deliver a total dose of 75 J/cm2 
(peak wavelength 640 nm, FWHM 25 nm). The Ambulight device has a green light displayed 
when device is active. A red light will be displayed if the device is not working properly. The 
green light will go off at the end of the planned automated treatment time. The patient will be 
free to go home once the cream and device are in place and will be advised about how to 
remove the plaster at the end of the irradiation period. The battery pack and used adhesive 
plaster are put in  bags and then in the pre-paid envelope (supplied by the treatment centre) 
and posted back to the Photobiology Unit where the battery pack will be cleaned, recharged and 
re-calibrated and the dressing head sent back to the manufacturer for recycling. 
 
Assessments      (Appendix 1 and 2) 
Re-treatment and assessment: Seven days later the patient will return for the second treatment, 
which will be repeated as per the first week and the treatment allocation. Prior to the second 
treatment, patients will be asked to complete a VAS score of 0 - 10 cm for the maximal recall of 
pain and discomfort experienced during the first PDT treatment.  Additionally, the phototoxic 
reaction of the first treatment will also be assessed on a semi-quantitative scale for erythema (0-
3), oedema (0-1), blistering (0-1), crusting (0-1) and ulceration (0-1) at this time point.  This 
second treatment then completes the first treatment cycle. 
 
Follow-up assessment at one week: The patient will return one week later and, again, pain and 
phototoxicity will be assessed as above. 
 
Follow-up assessment at three months: Patients will be reviewed at three months and a clinical 
assessment of whether there is clearance (defined as absence of residual surface change, 
scale, infiltration or significant erythema) (CR), partial response (presence of residual surface 
change, scale, infiltration or prominent erythema) (PR) or no response (no change from baseline 
appearance) (NR) will be made.  For patients with PR or NR a second treatment cycle will be 
performed according to the original randomisation.  Again, pain recall and phototoxicity will be 
assessed one week after each of these treatments as per the first treatment cycle.   
 
Follow-up assessment at six months: All patients will receive a follow-up assessment at 6 
months.  Those who do not exhibit a complete response on clinical assessment (after one or 
two treatment cycles) will receive an alternative treatment at the doctor’s discretion and the 
patient will have completed the study. An overall assessment of the patient’s evaluation of 
treatment will also be recorded in all patients’s notes at this time point.  This evaluation will take 
into account the patient’s perception of efficacy, adverse effects and convenience of treatment 
and their overall satisfaction with the PDT regime they received.   
 
Follow-up assessment at 12 months: All patients remaining in the study (i.e. those with CR at 3 
months and/or 6 months) will undergo final clinical assessment of efficacy of treatment (clear or 
not clear) at 12 months after the first PDT treatment cycle.  Histological analysis will not be  
undertaken as part of the study as these patients will usually have been selected for PDT on the 
basis that surgery was not considered appropriate. 
 
Data processing and statistical analysis 
Stastistical power:  From our original published data with the prototype device, the mean pain 
score of patients treated with ambulatory low irradiance PDT (n=12) was 1.25 (standard 
deviation 0.4) and was 5.26 (standard deviation 2.38) for a historical cohort of patients treated 

ambvconv/jg/v.4                                                                                                           02/05/2012 
 
with conventional PDT (n=50) (10).  Based on this we estimated that to give 90% power to 
detect as significant at the 5% level (p<0.05 as significant), a difference in mean pain score in 
one group of 2 compared with the mean pain score of 4 in the other group, assuming two-sided 
testing, a minimum of 36 subjects would be needed.  Therefore, we plan to incorporate a safety 
margin recruiting 50 subjects given the old and frail nature of patients as this would account for 
any drop-outs.  Over the last 2 years, we have treated 60 - 80 new patients per year with topical 
PDT.  82% of these were patients with Bowen’s disease or superficial basal cell carcinoma and 
we estimate that of these at least 50% should fit the eligibility criteria for the study.  Therefore, 
we estimate that recruitment will be finished within 2 years, and with a one year follow-up, the 
overall study will be completed within 3 years. 
 
Blinding: Blinding of the patient and the Photobiology technician will not be possible.  The study 
will remain blinded to the CI and co-investigators until database lock, after which the study 
statistician will be unblinded.  Any necessary clinical communications will be carried out by a 
Photobiology Unit clinician unrelated to the study. These clinicians will be the photodermatology 
Specialist Registrars. 
 
Data recording and analysis: Analyses will involve assessment of tabulated and graphical data 
and this will be followed by use of appropriate statistical tests comparing the pre-planned 
outcome measures.  Analysis will be on an intention-to-treat basis, where possible. Reporting of 
study data will be based on CONSORT guidance. 
 
Timetable of work 
Patient recruitment will be completed by the end of year 2 and follow up by the end of year 3.  
Final analysis of outcome measures will be undertaken in year 3. 
 
Key references 
1. 
Jung GW, Metelista AI, Dover DC et al.  Trends in incidence of nonmelanoma skin cancers 
in Alberta, Canada, 1988-2007.  Br J Dermatol 2010; 163:146-154 
2. 
Kennedy JC, Pottier RH, Pross DC.  Photodynamic therapy with endogenous 
proptoporphyrin IX: basic principles and present clinic experience.  J Photochem Photobiol 
B Biol 1990; 6: 143-148 
3. 
Braathen LR, Szeimies R-M, Basset-Sequin N et al.  Guidelines on the use of 
photodynamic therapy for nonmelanoma skin cancer: an international consensus.  J Am 
Acad Dermatol 2007; 56: 125-143 
4. 
Morton CA, McKenna KE, Rhodes LE et al.  Guidelines for topical photodynamic therapy: 
an update.  Br J Dermatol 2008; 159: 1245-1266 
5. 
Warren CB, Laszlo JK, Vidimos A et al. Pain associated with aminolevulinic acid-
photodynamic therapy of skin disease.  J Am Acad Dermatol 2009; 61: 1033-1043. 
6. 
Holmes MV, Dawe RS, Ferguson J et al.  A randomized, double-blind, placebo-controlled 
study of the efficacy of tetracaine gel (Ametop) for pain relief during topical photodynamic 
therapy.  Br J Dermatol 2004; 150: 337-340 
7. 
Langan SM, Collins P. Randomized, double-blind, placebo-controlled prospective study of 
the efficacy of topical anaesthesia with a eutetic mixture of lignocaine 2.5% and prilocaine  
8. 
2.5% for topical 5-aminolaevulinic acid-photodynamic therapy for extensive scalp actinic 
keratosis.  Br J Dermatol 2006; 154: 146-9 
9. 
Cottrell WJ, Paquette AD, Keymel KR et al.  Irradiance-dependent photobleaching and pain 
in delta-aminolevulinic acid-photodynamic of superficial basal cell carcinomas.  Clin Cancer 
Res 2008; 14: 4475-4483 

ambvconv/jg/v.4                                                                                                           02/05/2012 
 
10. Attili SK, Lesar A, McNeill A et al.  An open pilot study of ambulatory photodynamic therapy 
using a wearable low-irradiance organic light-emitting diode light source in the treatment of 
nonmelanoma skin cancer.  Br J Dermatol 2009; 161: 170-173  
11. Langmack K, Mehta R, Twyman P et al.  Topical photodynamic therapy at low fluence rates 
– theory and practice.  J Photochem Photobiol B Biol 2001; 60: 37-43 
12. Wiegell SR, Haedersdal M, Philipsen PA et al.  Continuous activation of PpIX by daylight is 
as effective as and less painful than conventional photodynamic therapy for actinic 
keratoses: a randomized, controlled, single-blinded study.  Br J Dermatol 2008; 158: 740-
746 
13. Moseley H, Allen JW, Ibbotson SH et al.  Ambulatory photodynamic therapy: a new concept 
in delivering photodynamic therapy.  Br J Dermatol 2006; 154: 747-750 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ambvconv/jg/v.4                                                                                                           02/05/2012 
 
 
Week 0 
Ambulight PDT 
Week 0 
Conventional PDT 
Week 1 
Pain/phototoxicity assessment 
Conventional PDT 
Week 12 
Assess Response 
Patients with NMSC recruited to 
study 
Week 2 
Pain/phototoxicity assessment 
Clear 
Not clear 
Ambulight PDT 
Not Clear 
Conventional PDT 
Clear 
Week 13 
Pain/phototoxicity assessment 
Ambulight PDT 
Week 14 
Pain/phototoxicity assessment 
6 months 
Assessment of efficacy 
Patient evaluation 
questionnaire 
Week 13 
Pain/phototoxicity assessment 
Conventional PDT 
Week 14 
Pain/phototoxicity assessment 
6 months 
Assessment of efficacy 
Patient evaluation 
questionnaire 
Clear 
Not clear 
Not clear 
Clear 
Other treatment at the doctor’s 
discretion 
Study complete 
12 months 
Assessment of efficacy 
Patient evaluation questionnaire 
Study complete 
12 months 
Assessment of efficacy 
Patient evaluation questionnaire 
Study complete 
Week 1 
Pain/phototoxicity assessment 
Ambulight PDT 
Week 2 
Pain/phototoxicity assessment 
Appendix 1 
Week 12 
Assess Response 

ambvconv/jg/v.4                                                                                                           02/05/2012 
 
Treatment very 
poor and I would 
not have again 
Treatment 
excellent and I 
would have again 
 
 
Appendix 2                                                         Study I.D.  
 
A randomised controlled trial of ambulatory low irradiance PDT and 
conventional PDT for superficial non-melanoma skin cancer 
 
Questionnaire: Patient evaluation of treatment regime 
 
 
A. Effectiveness of treatment 
1. NR – No response, not effective 
2. PR – Partial response, partially effective 
3. CR – complete response, completely effective 
 
 
B. Side effects of treatment – e.g. pain and inflammation 
1. Severe 
2. Moderate 
3. Mild 
4. None/minimal 
 
 
C. Practicalities of treatment – e.g. ease of use, travel, time, inconvenience 
1. Very disruptive and difficult 
2. Moderately disruptive and difficult 
3. Minimally disruptive and difficult 
 
 
Total minimum score: 3 
Total maximum score: 10 
 
 
Overall patient evaluation: 
 
How would you rate treatment overall? 
 
Please indicate by scoring across the line below between 0 to 10 
 
 
        0  
10